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188 results on '"Institut Clinique de la Souris (ICS)"'

1. High-throughput discovery of novel developmental phenotypes.

Author: Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie, Sarah M, Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Newbigging, Susan, Nutter, Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, Bućan, Maja, and Murray, Stephen A
Subjects: International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris, Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Disease, Imaging, Three-Dimensional, Conserved Sequence, Sequence Homology, Phenotype, Penetrance, Mutation, Polymorphism, Single Nucleotide, Genes, Essential, Genes, Lethal, Embryo, Mammalian, Genome-Wide Association Study, High-Throughput Screening Assays, Biotechnology, Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, 2.1 Biological and endogenous factors, General Science & Technology
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
Published: 2016

2. Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice

Author: Jean-Loup Duband, Marie-France Champy, Marie-Christine Birling, Hamid Meziane, Evelyne Bloch-Gallego, Isabelle Janoueix-Lerosey, Thomas Bourgeois, Olivier Delattre, Jorge Gallego, Michel Huerre, Tania Sorg, Michel Roux, Boris Matrot, Lucille Lopez-Delisle, Estelle Durand, Cécile Pierre-Eugène, Bos, Mireille, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), PhenoPups : Preclinical Pediatric Contract Research Organization [Evry], Phenopups SAS [Evry], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie, Institut Curie [Paris], The U830 Inserm laboratory is supported bygrants from the Institut National du Cancer, the LigueNationale contre le Cancer (Equipe labellisée), theAssociation Hubert Gouin, Les Bagouz à Manon, les amisde Claire, la Fédération Enfants et Santé et la SociétéFrançaise de Lutte contre les Cancers et les Leucémiesde l’Enfant et l’Adolescent. L. L.-D. is the recipient ofa fellowship of the Ecole Polytechnique. The InstitutClinique de la Souris was funded by Inserm., Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Clinique de la Souris ( ICS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie du Développement ( LBD ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and INSTITUT CURIE
Subjects: Male, Congenital neuroblastoma, MESH : Behavior, Animal, MESH: Eating, Germline, MESH: Animals, Newborn, Feeding difficulty, brainstem, Immunoenzyme Techniques, Eating, Mice, Neuroblastoma, 0302 clinical medicine, neonatal lethality, hemic and lymphatic diseases, MESH: Behavior, Animal, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, MESH: Animals, feeding difficulties, 0303 health sciences, Behavior, Animal, plethysmography, MESH : Animals, Newborn, Respiration, 3. Good health, MESH : Phenotype, Phenotype, Oncology, 030220 oncology & carcinogenesis, Neonatal lethality, MESH: Receptor Protein-Tyrosine Kinases, MESH : Mutation, Research Paper, medicine.medical_specialty, MESH : Eating, MESH: Mutation, MESH : Male, Biology, MESH: Phenotype, 03 medical and health sciences, Germline mutation, MESH : Immunoenzyme Techniques, Internal medicine, Gene knockin, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, In patient, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Immunoenzyme Techniques, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Gynecology, MESH: Respiration, MESH: Humans, MESH : Humans, Receptor Protein-Tyrosine Kinases, MESH : Receptor Protein-Tyrosine Kinases, MESH: Neuroblastoma, MESH: Male, MESH : Respiration, Endocrinology, Animals, Newborn, ALK, MESH : Genes, Lethal, Mutation, MESH : Neuroblastoma, Genes, Lethal, MESH : Animals, MESH: Genes, Lethal
Abstract: // Lucille Lopez-Delisle 1,2 , Cecile Pierre-Eugene 1,2 , Evelyne Bloch-Gallego 3,4 , Marie-Christine Birling 5 , Jean-Loup Duband 6,7 , Estelle Durand 8 , Thomas Bourgeois 8 , Boris Matrot 8,9 , Tania Sorg 5 , Michel Huerre 10 , Hamid Meziane 5 , Michel J. Roux 5 , Marie-France Champy 5 , Jorge Gallego 9 , Olivier Delattre 1,2 , Isabelle Janoueix-Lerosey 1,2 1 Inserm U830, Paris, France; 2 Institut Curie, Centre de Recherche, Paris, France; 3 Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, France; 4 Inserm, U1016, Paris, France; 5 Institut Clinique de la Souris, Illkirch-Graffenstaden, France; 6 Sorbonne Universites, Universite Pierre et Marie Curie-Paris 6, Paris, France; 7 CNRS, Laboratoire de Biologie du Developpement, Paris, France; 8 PhenoPups SAS, Evry, France; 9 Inserm U1141, Hopital Robert Debre, Paris, France; 10 Institut Curie, Departement de Pathologie, Paris, France. Correspondence: Isabelle Janoueix-Lerosey, email: // Keywords : ALK, brainstem, neonatal lethality, plethysmography, feeding difficulties Received : March 24, 2014 Accepted : April 01, 2014 Published : April 02, 2014 Abstract The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the Alk F1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
Published: 2014
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3. Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment

Author: Wenjin Yao, Beatriz German, Dounia Chraa, Antoine Braud, Cecile Hugel, Pierre Meyer, Guillaume Davidson, Patrick Laurette, Gabrielle Mengus, Eric Flatter, Pierre Marschall, Justine Segaud, Marine Guivarch, Pierre Hener, Marie-Christine Birling, Dan Lipsker, Irwin Davidson, Mei Li, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Institut Clinique de la Souris (ICS), ANR-19-CE17-0017,TARGET-NS,Développement d'une nouvelle biothérapie ciblant les mécanismes inflammatoires du syndrome de Netherton(2019), ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), ANR-17-EURE-0023,IMCBio,Integrative Molecular and Cellular Biology(2017), MENGUS, Gabrielle, Développement d'une nouvelle biothérapie ciblant les mécanismes inflammatoires du syndrome de Netherton - - TARGET-NS2019 - ANR-19-CE17-0017 - AAPG2019 - VALID, Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Façonner les talents en formation et en recherche à l'Université de Strasbourg - - STRAT'US2020 - ANR-20-SFRI-0012 - SFRI - VALID, and Integrative Molecular and Cellular Biology - - IMCBio2017 - ANR-17-EURE-0023 - EURE - VALID
Subjects: Keratinocytes, [SDV] Life Sciences [q-bio], Mice, Skin Neoplasms, Thymic Stromal Lymphopoietin, [SDV]Life Sciences [q-bio], Tumor Microenvironment, Humans, Animals, Cytokines, General Medicine, Melanoma
Abstract: International audience; Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge lies in better understanding how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by the tumor microenvironment. Here, we show that expression of the cytokine thymic stromal lymphopoietin (TSLP) by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP-KO or overexpression, we defined a crosstalk between melanoma cells, keratinocytes, and immune cells in establishing a tumor-promoting microenvironment. Keratinocyte-derived TSLP is induced by signals derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLP receptor-expressing (TSLPR-expressing) DCs to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4, and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFN-γ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Our study provides insights into the role of TSLP in programming a protumoral immune microenvironment in cutaneous melanoma.
Published: 2022
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4. Absence of TI-VAMP/Vamp7 leads to increased anxiety in mice

Author: Guillaume Pavlovic, F. Trovero, Tania Sorg, Floriana Della Ragione, Maurizio D'Esposito, Thierry Galli, Véronique Proux-Gillardeaux, Lydia Danglot, Kathleen Zylbersztejn, Marie-France Champy, Denis Vivien, Maja Petkovic, Jean-Charles Bizot, Hamid Meziane, Marie-Christine Birling, Roy Combe, Maxime Gauberti, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), INSERM ERL U950, Membrane Traffic in Neuronal and Epithelial Morphogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Clinique de la Souris (ICS), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Key-Obs, Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche (CNR), Inserm, Association Francaise contre les Myopathies, Association pour la Recherche sur le Cancer, Mairie de Paris, Medical Research and Health Program, Fondation pour la Recherche Medicale (FRM), Ecole des Neurosciences de Paris (ENP), CNRS, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Roma 'La Sapienza' [Rome]-Università degli studi di Napoli Federico II, Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Clinique de la Souris ( ICS ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Istituto Neurologico Mediterraneo ( NEUROMED I.R.C.C.S. ), Consiglio Nazionale delle Ricerche ( CNR ), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)
Subjects: Male, MESH: R-SNARE Proteins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Rabbits, Behavioral neuroscience, Anxiety, MESH: Mice, Knockout, MESH : Mice, 129 Strain, R-SNARE Proteins, Exon, Mice, 0302 clinical medicine, MESH : Anxiety, Chlorocebus aethiops, MESH: Animals, Cells, Cultured, Mice, Knockout, 0303 health sciences, MESH : R-SNARE Proteins, General Neuroscience, Metalloendopeptidases, Cell biology, MESH: COS Cells, medicine.anatomical_structure, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Metalloendopeptidases, COS Cells, Rabbits, SNARE complex, MESH : COS Cells, Brief Communications, MESH: Cells, Cultured, Cell type, Mice, 129 Strain, MESH : Male, MESH: Metalloendopeptidases, MESH : Mice, Inbred C57BL, Biology, Exocytosis, 03 medical and health sciences, MESH: Mice, 129 Strain, Tetanus Toxin, MESH: Mice, Inbred C57BL, MESH : Cells, Cultured, MESH : Mice, medicine, Animals, MESH : Rabbits, MESH: Tetanus Toxin, MESH: Mice, 030304 developmental biology, Third ventricle, MESH: Anxiety, Lipid bilayer fusion, MESH : Tetanus Toxin, MESH: Cercopithecus aethiops, MESH: Male, Mice, Inbred C57BL, Membrane protein, MESH : Mice, Knockout, MESH : Animals, MESH : Cercopithecus aethiops, Neuroscience, 030217 neurology & neurosurgery
Abstract: Vesicular (v)- and target (t)-SNARE proteins assemble in SNARE complex to mediate membrane fusion. Tetanus neurotoxin-insensitive vesicular-associated membrane protein (TI-VAMP/VAMP7), a vesicular SNARE expressed in several cell types including neurons, was previously shown to play a major role in exocytosis involved in neurite growth in cultured neurons. Here we generated a complete constitutive knock-out by deleting the exon 3 ofVamp7. Loss of TI-VAMP expression did not lead to any striking developmental or neurological defect. Knock-out mice displayed decreased brain weight and increased third ventricle volume. Axon growth appeared normal in cultured knock-out neurons. Behavioral characterization unraveled that TI-VAMP knock-out was associated with increased anxiety. Our results thus suggest compensatory mechanisms allowing the TI-VAMP knock-out mice to fulfill major developmental processes. The phenotypic traits unraveled here further indicate an unexpected role of TI-VAMP-mediated vesicular traffic in anxiety and suggest a role for TI-VAMP in higher brain functions.
Published: 2012
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5. Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice

Author: Roberto Silva-Rojas, Laura Pérez-Guàrdia, Emma Lafabrie, David Moulaert, Jocelyn Laporte, Johann Böhm, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), and Laporte, Jocelyn
Subjects: STIM1, mouse model, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Catalysis, Inorganic Chemistry, shRNA, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], muscle disorder, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, calcium, Organic Chemistry, tubular aggregate myopathy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Computer Science Applications, ORAI1, Stormorken syndrome, ion channel, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract: International audience; Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca2+ entry due to gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1R304W/+ mice with Orai1+/− mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1R304W/+Orai1+/− mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1R304W/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1R304W/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues.
Published: 2022
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6. Contribution of gene-modified mice and rats to our understanding of the cardiovascular pharmacology of serotonin

Author: Marc André Laplante, Stéphane Doly, Tarak Ayadi, Luc Maroteaux, Laurent Monassier, Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire [UNIV Strasbourg] (PMT EA 4438), Université de Strasbourg (UNISTRA), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by funds from the Centre National de la Recherche Scientiﬁque, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the Association pour la Recherche contre le Cancer, the French ministry of research (Agence Nationale pour la Recherche), and the European Commission (FP7-health-2007-A-201714). LMa's team is an 'Equipe Fondation pour la Recherche Médicale' and S. Doly is supported by a Lefoulon-Lalande fellowship., ANR: SEROCARD, trans-SERT,SEROCARD, trans-SERT, European Project: 201714,HEALTH,FP7-HEALTH-2007-A,DEVANX(2008), Régulation nerveuse de la fonction cardiovasculaire, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Clinique de la Souris ( ICS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR : SEROCARD, European Project : 201714,HEALTH,FP7-HEALTH-2007-A,DEVANX ( 2008 ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-05-NEUR-0046,trans-SERT,Fonction et régulation de l'expression transitoire du transporteur de la sérotonine dans les neurones glutamatergiques.(2005)
Subjects: Blood Platelets, medicine.medical_specialty, hypertension, pulmonary, Transgene, Mutant, Cardiovascular Abnormalities, 030204 cardiovascular system & hematology, Rats, Mutant Strains, Animals, Genetically Modified, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Cardiac conduction, medicine, Animals, Pharmacology (medical), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptor, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, development, Serotonin transporter, 030304 developmental biology, Pharmacology, Mice, Knockout, 0303 health sciences, biology, cardiac hypertrophy, Cardiovascular Agents, Heart, cytokines, 3. Good health, Rats, serotonin, Monoamine neurotransmitter, Endocrinology, Cardiovascular Diseases, Receptors, Serotonin, biology.protein, Receptor, Serotonin, 5-HT1B, hemostasis, Serotonin, Serotonin Degradation
Abstract: International audience; This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for tryptophan hydroxylase 1 and lacking peripheral serotonin, or mutant for 5-HT(2B) receptors, display cardiac defects and dilated cardiomyopathy. The 5-HT(4) receptor is important for the maturation of cardiac conduction. In fact, transgenic approaches have revealed that adult cardiac status is strongly influenced by maternal serotonin. Serotonin has long been known to be a vasoconstrictor in adult physiology. Analysis of animals knocked-out for the serotonin transporter suggested a role in blood pressure control and revealed an effect of 5-HT(2B) receptor antagonists in hypertension. In the lung vasculature, mice lacking the 5-HT(2B) receptor gene that are exposed to chronic hypoxia are resistant to pulmonary hypertension, while 5-HT(1B) receptor and serotonin transporter mutant animals show partial resistance. In platelets, mutant mice revealed that serotonin transporter regulates not only the mechanisms by which serotonin is packaged and secreted but also platelet aggregation. Studies looking at adult cardiac remodeling showed that mice lacking the 5-HT(2B) receptor gene were protected from cardiac hypertrophy. Their fibroblasts were unable to secrete cytokines. Crossing these animals with mice overexpressing the receptor in cardiomyocytes revealed the contribution of cardiac fibroblasts and 5-HT(2B) receptors to cardiac hypertrophy. In mice lacking the monoamine oxidase-A gene, the role of serotonin degradation in cardiac hypertrophy was confirmed. Works with gene-modified animals has contributed strongly to the re-evaluation of the influence of serotonin on cardiovascular regulation, though several unknowns remain to be investigated.
Published: 2010
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7. Site-specific recombinases for manipulation of the mouse genome

Author: Marie-Christine Birling, Xavier Warot, Françoise Gofflot, Institut Clinique de la Souris ( ICS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Peney, Maité, Institut Clinique de la Souris (ICS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: media_common.quotation_subject, MESH : Animals, Genetically Modified, Mutagenesis (molecular biology technique), Computational biology, Biology, MESH: Gene Targeting, Genome, MESH : Genetic Engineering, Animals, Genetically Modified, MESH: Animals, Genetically Modified, 03 medical and health sciences, Mice, 0302 clinical medicine, MESH : DNA Nucleotidyltransferases, MESH : Mice, Recombinase, Animals, MESH: Animals, MESH: Genome, Function (engineering), Gene, MESH: Mice, 030304 developmental biology, media_common, MESH: Mutagenesis, Genetics, 0303 health sciences, Recombinase-mediated cassette exchange, MESH: DNA Nucleotidyltransferases, Gene targeting, food and beverages, MESH : Mutagenesis, Workflow, Mutagenesis, DNA Nucleotidyltransferases, Gene Targeting, MESH: Genetic Engineering, MESH : Animals, Genetic Engineering, MESH : Genome, 030217 neurology & neurosurgery, MESH : Gene Targeting
Abstract: International audience; Site-specific recombination systems are widespread and popular tools for all scientists interested in manipulating the mouse genome. In this chapter, we focus on the use of site-specific recombinases (SSR) to unravel the function of genes of the mouse. In the first part, we review the most commonly used SSR, Cre and Flp, as well as the newly developed systems such as Dre and PhiC31, and we present the inducible SSR systems. As experience has shown that these systems are not as straightforward as expected, particular attention is paid to facts and artefacts associated with their production and applications to study the mouse genome. In the next part of this chapter, we illustrate new applications of SSRs that allow engineering of the mouse genome with more and more precision, including the FLEX and the RMCE strategies. We conclude and suggest a workflow procedure that can be followed when using SSR to create your mouse model of interest. Together, these strategies and procedures provide the basis for a wide variety of studies that will ultimately lead to the analysis of the function of a gene at the cellular level in the mouse.
Published: 2009
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8. Molecular Networking-Based Approach of Aloe djiboutiensis, Antioxidant Activity and In Vivo Toxicity of This Endemic Species in Djibouti

Author: Spina, Rosella, Elmi, Abdirahman, Mohamed Abdoul-Latif, Fatouma, Dupire, François, Philippot, Stéphanie, Champy, Marie-France, Petit-Demoulière, Benoît, Jacobs, Hugues, Laurain-Mattar, Dominique, Spina, Rosella, Laboratoire Agronomie et Environnement (LAE), Université de Lorraine (UL)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire Lorrain de Chimie Moléculaire (L2CM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherche de Djibouti (CERD), Institut Clinique de la Souris (ICS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [CHIM] Chemical Sciences, [CHIM]Chemical Sciences
Abstract: International audience
Published: 2022

9. Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

Author: Yann Herault, Véronique Brault, Marie-Christine Birling, Spiros D. Garbis, Tania Sorg, Eugene Yu, Antigoni Manousopoulou, Valérie Lalanne, Guillaume Pavlovic, Javier Flores-Gutiérrez, Loic Lindner, Giovanni Iacono, Thu Lan Nguyen, Hamid Meziane, Mohammed Selloum, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, Cancer Research, Microcephaly, Transcription, Genetic, DYRK1A, [SDV]Life Sciences [q-bio], Gene Dosage, Social Sciences, Hippocampus, QH426-470, Synaptic Transmission, DYRK1A Gene, Mice, Cognition, Learning and Memory, 0302 clinical medicine, Animal Cells, Conditional gene knockout, Medicine and Health Sciences, Psychology, Genetics (clinical), Neurons, Mammals, 0303 health sciences, Animal Behavior, Genetically Modified Organisms, Brain, Eukaryota, Animal Models, 3. Good health, Experimental Organism Systems, Vertebrates, Long Term Memory, Engineering and Technology, Cellular Types, Anatomy, Genetic Engineering, Research Article, Biotechnology, Genetically modified mouse, Down syndrome, Cognitive Neuroscience, Glutamic Acid, Mouse Models, Bioengineering, Mice, Transgenic, Biology, Research and Analysis Methods, Rodents, Speech Disorders, 03 medical and health sciences, Glutamatergic, Model Organisms, Memory, Intellectual Disability, Genetics, medicine, Animals, Humans, Working Memory, Autistic Disorder, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Behavior, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetically Modified Animals, [SCCO.NEUR]Cognitive science/Neuroscience, Organisms, Biology and Life Sciences, Cell Biology, medicine.disease, Disease Models, Animal, Gene Expression Regulation, Cellular Neuroscience, Amniotes, Synaptic plasticity, Animal Studies, Cognitive Science, Down Syndrome, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cognition Disorders, Zoology, Neuroscience, 030217 neurology & neurosurgery
Abstract: Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach., Author summary The Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A, DYRK1A, drives cognitive alterations with increased dose in Down syndrome (DS) or with reduced dose in DYRK1A-related intellectual disability syndromes (ORPHA:268261; ORPHA:464311) also known as mental retardation, autosomal dominant disease 7 (MRD7; OMIM #614104). Here we report that specific and complete loss of Dyrk1a in glutamatergic neurons induced a range of specific cognitive phenotypes and alter the expression of genes involved in neurotransmission in the hippocampus. We further explored the consequences of Dyrk1a dosage in glutamatergic neurons on the cognitive phenotypes observed respectively in MRD7 and DS mouse models and we found specific roles in long-term explicit memory with no impact on motor activity, short-term working memory, and susceptibility to epilepsy. Then we demonstrated that DYRK1A is a component of the glutamatergic post-synapse and interacts with several component such as NR2B and PSD95. Altogether our work describes a new role of DYRK1A at the glutamatergic synapse that must be considered to understand the consequence of treatment targeting DYRK1A in disease.
Published: 2021
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10. Distinct roles of α‐ and β‐tubulin polyglutamylation in controlling axonal transport and in neurodegeneration

Author: Sudarshan Gadadhar, Maria M. Magiera, Marie-Christine Birling, Satish Bodakuntla, Mariya Genova, Dennis Klein, Carsten Janke, Sophie Leboucher, Xidi Yuan, Rudolf Martini, Intégrité du génome, ARN et cancer, Institut Curie [Paris]-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University Hospital of Würzburg, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Janke, Carsten
Subjects: [SDV]Life Sciences [q-bio], Motility, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Axonal Transport, Microtubules, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, Purkinje Cells, 0302 clinical medicine, Microtubule, Tubulin, medicine, Animals, Peptide Synthases, Polyglutamylation, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, General Immunology and Microbiology, General Neuroscience, Neurodegeneration, Neurodegenerative Diseases, Articles, medicine.disease, Cell biology, Mitochondria, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Polyglutamic Acid, Axoplasmic transport, biology.protein, Corrigendum, 030217 neurology & neurosurgery, Homeostasis
Abstract: Tubulin polyglutamylation is a post-translational modification of the microtubule cytoskeleton, which is generated by a variety of enzymes with different specificities. The "tubulin code" hypothesis predicts that modifications generated by specific enzymes selectively control microtubule functions. Our recent finding that excessive accumulation of polyglutamylation in neurons causes their degeneration and perturbs axonal transport provides an opportunity for testing this hypothesis. By developing novel mouse models and a new glutamylation-specific antibody, we demonstrate here that the glutamylases TTLL1 and TTLL7 generate unique and distinct glutamylation patterns on neuronal microtubules. We find that under physiological conditions, TTLL1 polyglutamylates α-tubulin, while TTLL7 modifies β-tubulin. TTLL1, but not TTLL7, catalyses the excessive hyperglutamylation found in mice lacking the deglutamylase CCP1. Consequently, deletion of TTLL1, but not of TTLL7, prevents degeneration of Purkinje cells and of myelinated axons in peripheral nerves in these mice. Moreover, loss of TTLL1 leads to increased mitochondria motility in neurons, while loss of TTLL7 has no such effect. By revealing how specific patterns of tubulin glutamylation, generated by distinct enzymes, translate into specific physiological and pathological readouts, we demonstrate the relevance of the tubulin code for homeostasis.
Published: 2021
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11. High Resolution Episcopic Microscopy for Qualitative and Quantitative Data in Phenotyping Altered Embryos and Adult Mice Using the New 'Histo3D' System

Author: James Mu, Thomas W. Rosahl, Didier Hentsch, Serge Taubert, Manuel Mark, Fabien Pertuy, Michela Di Michele, Jean-Luc Vonesch, Olivia Wendling, Hugues Jacobs, Laurent Le Cam, Nicolas Lemercier, Yann Herault, Tania Sorg, Mindy Liu, Ester Carballo-Jane, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Merck & Co. Inc, Les Hôpitaux Universitaires de Strasbourg (HUS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), Herault, Yann, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine - - INRT2010 - ANR-10-LABX-0030 - LABX - VALID, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: 0301 basic medicine, phenotyping, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, microanatomy, QH301-705.5, Medicine (miscellaneous), High resolution, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Histological staining, 03 medical and health sciences, 0302 clinical medicine, 3D imaging, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Microscopy, Rotary microtome, Computational analysis, Biology (General), [SDV.BDD]Life Sciences [q-bio]/Development Biology, Organ system, 3D reconstruction, Embryo, quantification, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, 030104 developmental biology, high-resolution episcopic microscopy, [SDV.BA.ZV] Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, 030217 neurology & neurosurgery, Biomedical engineering
Abstract: International audience; 3D imaging in animal models, during development or in adults, facilitates the identification of structural morphological changes that cannot be achieved with traditional 2D histological staining. Through the reconstruction of whole embryos or a region-of-interest, specific changes are better delimited and can be easily quantified. We focused here on high-resolution episcopic microscopy (HREM), and its potential for visualizing and quantifying the organ systems of normal and genetically altered embryos and adult organisms. Although the technique is based on episcopic images, these are of high resolution and are close to histological quality. The images reflect the tissue structure and densities revealed by histology, albeit in a grayscale color map. HREM technology permits researchers to take advantage of serial 2D aligned stacks of images to perform 3D reconstructions. Three-dimensional visualization allows for an appreciation of topology and morphology that is difficult to achieve with classical histological studies. The nature of the data lends itself to novel forms of computational analysis that permit the accurate quantitation and comparison of individual embryos in a manner that is impossible with histology. Here, we have developed a new HREM prototype consisting of the assembly of a Leica Biosystems Nanocut rotary microtome with optics and a camera. We describe some examples of applications in the prenatal and adult lifestage of the mouse to show the added value of HREM for phenotyping experimental cohorts to compare and quantify structure volumes. At prenatal stages, segmentations and 3D reconstructions allowed the quantification of neural tissue and ventricular system volumes of normal brains at E14.5 and E16.5 stages. 3D representations of normal cranial and peripheric nerves at E15.5 and of the normal urogenital system from stages E11.5 to E14.5 were also performed. We also present a methodology to quantify the volume of the atherosclerotic plaques of ApoEtm1Unc/tm1Unc mutant mice and illustrate a 3D reconstruction of knee ligaments in adult mice.
Published: 2021
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12. INFRAFRONTIER quality principles in systemic phenotyping

Author: Hilke Ehlich, Reetta Vuolteenaho, Michael Raess, Vasileios Ntafis, Ana Zarubica, Bernard Malissen, Dimitris L. Kontoyiannis, Mohammed Selloum, Tania Sorg, Ann M Flenniken, Martin Hrabě de Angelis, Claudia Stoeger, Yann Herault, Isabelle Goncalves Da Cruz, George Kollias, Sarka Suchanova, Heather Cater, Reetta Hinttala, Radislav Sedlacek, Sara Wells, Colin McKerlie, Anne-Marie Mura, Steve D.M. Brown, Jan Rozman, MRC Harwell Institute [UK], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alexander Fleming Biomedical Sciences Research Center, Partenaires INRAE, Helmholtz-Zentrum München (HZM), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), University of Oulu, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Technische Universität München [München] (TUM), The Hospital for sick children [Toronto] (SickKids), University of Toronto, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), INFRAFRONTIER GmbH [Neuherberg], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), and Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: Service (systems architecture), media_common.quotation_subject, [SDV]Life Sciences [q-bio], Interoperability, Context (language use), Biology, 03 medical and health sciences, Preclinical research, Mice, 0302 clinical medicine, Genetics, Animals, Quality (business), 030304 developmental biology, media_common, Mammals, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genome, European research, [SDV.BA]Life Sciences [q-bio]/Animal biology, Reproducibility of Results, Internal quality, Disease Models, Animal, Risk analysis (engineering), Key (cryptography), 030217 neurology & neurosurgery
Abstract: Improving reproducibility and replicability in preclinical research is a widely discussed and pertinent topic, especially regarding ethical responsibility in animal research. INFRAFRONTIER, the European Research Infrastructure for the generation, phenotyping, archiving, and distribution of model mammalian genomes, is addressing this issue by developing internal quality principles for its different service areas, that provides a quality framework for its operational activities. This article introduces the INFRAFRONTIER Quality Principles in Systemic Phenotyping of genetically altered mouse models. A total of 11 key principles are included, ranging from general requirements for compliance with guidelines on animal testing, to the need for well-trained personnel and more specific standards such as the exchange of reference lines. Recently established requirements such as the provision of FAIR (Findable, Accessible, Interoperable, Reusable) data are also addressed. For each quality principle, we have outlined the specific context, requirements, further recommendations, and key references.
Published: 2021
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13. Severe head dysgenesis resulting from imbalance between anterior and posterior ontogenetic programs

Author: Emmanuelle, Grall, Victor, Gourain, Asmaa, Naïr, Elisabeth, Martin, Marie-Christine, Birling, Jean-Noël, Freund, Isabelle, Duluc, univOAK, Archive ouverte, Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Institute of Toxicology and Genetics [Karlsruhe] (ITG), Karlsruhe Institute of Technology (KIT), Institut Clinique de la Souris (ICS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Life sciences, biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Disease model, lcsh:Cytology, Gastrulation, Genes, Homeobox, Embryonic Development, Gene Expression Regulation, Developmental, [SDV.GEN] Life Sciences [q-bio]/Genetics, Article, Craniofacial Abnormalities, Mice, Prosencephalon, Neural Crest, ddc:570, embryonic structures, Morphogenesis, Animals, Humans, CDX2 Transcription Factor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, lcsh:QH573-671, Head
Abstract: Head dysgenesis is a major cause of fetal demise and craniofacial malformation. Although mutations in genes of the head ontogenetic program have been reported, many cases remain unexplained. Head dysgenesis has also been related to trisomy or amplification of the chromosomal region overlapping the CDX2 homeobox gene, a master element of the trunk ontogenetic program. Hence, we investigated the repercussion on head morphogenesis of the imbalance between the head and trunk ontogenetic programs, by means of ectopic rostral expression of CDX2 at gastrulation. This caused severe malformations affecting the forebrain and optic structures, and also the frontonasal process associated with defects in neural crest cells colonization. These malformations are the result of the downregulation of genes of the head program together with the abnormal induction of trunk program genes. Together, these data indicate that the imbalance between the anterior and posterior ontogenetic programs in embryos is a new possible cause of head dysgenesis during human development, linked to defects in setting up anterior neuroectodermal structures.
Published: 2019
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14. Genetic quality assurance and genetic monitoring of laboratory mice and rats: FELASA Working Group Report

Author: Yann Herault, Dirk Wedekind, Fernando Benavides, James Bussell, Ferdinando Scavizzi, Paolo Cinelli, Thomas Rülicke, Jan-Bas Prins, Directors's Laboratory, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hannover Medical School [Hannover] (MHH), University of Zurich, and Benavides, Fernando
Subjects: 3400 General Veterinary, 610 Medicine & health, Context (language use), Animal facilities, Computational biology, Biology, Mice, 03 medical and health sciences, Working Party Report, 0302 clinical medicine, Animal model, Inbred strain, Laboratory Animal Science, Animals, Laboratory, Genetic contamination, Animals, genetics, refinement, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, General Veterinary, business.industry, [SDV.BA]Life Sciences [q-bio]/Animal biology, Rats, 10021 Department of Trauma Surgery, rodents, Animal Science and Zoology, 1103 Animal Science and Zoology, quality assurance/control, business, Quality assurance, 030217 neurology & neurosurgery, Genetic composition, Genetic monitoring
Abstract: Genetic quality assurance (QA), including genetic monitoring (GeMo) of inbred strains and background characterization (BC) of genetically altered (GA) animal models, should be an essential component of any QA programme in laboratory animal facilities. Genetic quality control is as important for ensuring the validity of the animal model as health and microbiology monitoring are. It should be required that studies using laboratory rodents, mainly mice and rats, utilize genetically defined animals. This paper, presented by the FELASA Working Group on Genetic Quality Assurance and Genetic Monitoring of Laboratory Murines, describes the objectives of and available methods for genetic QA programmes in rodent facilities. The main goals of any genetic QA programme are: (a) to verify the authenticity and uniformity of inbred stains and substrains, thus ensuring a genetically reliable colony maintenance; (b) to detect possible genetic contamination; and (c) to precisely describe the genetic composition of GA lines. While this publication focuses mainly on mouse and rat genetic QA, the principles will apply to other rodent species some of which are briefly mentioned within the context of inbred and outbred stocks.
Published: 2019
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15. Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity

Author: Sander Kooijman, Yuanqing Gao, Anne-Laurence Boutillier, Samantha E C Wolff, Irina Milanova, Xiao-Lan Wang, Benoit Petit-Demoulière, Tania Sorg-Guss, Jean-Christophe Cassel, Isabelle Goncalves Da Cruz, Nikita L. Korpel, Chun-Xia Yi, Andries Kalsbeek, Patrick C.N. Rensen, Marie-France Champy, Laura Tzeplaeff, Brigitte Cosquer, Graduate School, ANS - Cellular & Molecular Mechanisms, ANS - Compulsivity, Impulsivity & Attention, ANS - Neuroinfection & -inflammation, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Endocrinology, Endocrinology Laboratory, Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Amsterdam [Amsterdam] (UvA), Leiden University Medical Center (LUMC), Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte
Subjects: 0301 basic medicine, Cell biology, Pro-Opiomelanocortin, Phagocytosis, Hippocampus, Biology, Diet, High-Fat, Energy homeostasis, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Memory, Stress, Physiological, medicine, Animals, Learning, Circadian rhythm, Obesity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Microglia, ARNTL Transcription Factors, Adaptive response, Circadian Rhythm, CLOCK, Mice, Inbred C57BL, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, Gene Knockdown Techniques, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, Function (biology)
Abstract: Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.
Published: 2021
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16. Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

Author: Hamid Meziane, Maria del Mar Muniz Moreno, Marcia Priscilla Silva de Souza, Valérie Nalesso, Jean-Paul Armspach, Yann Herault, Vincent Noblet, Véronique Brault, Sandra Martin Lorenzo, Claire Chevalier, Paulo Loureiro de Sousa, Arnaud Duchon, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), European Project: 848077,GO-DS21, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BRAULT, Véronique
Subjects: AcademicSubjects/SCI01140, 0301 basic medicine, Down syndrome, Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], RHOA, DYRK1A, mouse model, [SDV]Life Sciences [q-bio], Mice, Transgenic, Biology, Hippocampus, partial trisomy 21, memory, Mice, 03 medical and health sciences, Cognition, 0302 clinical medicine, Chromosome 16, genotype-phenotype maps, Gene interaction, Down syndrome critical region, Intellectual disability, Basic Helix-Loop-Helix Transcription Factors, Genetics, medicine, Animals, Molecular Biology, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, learning, [SCCO.NEUR]Cognitive science/Neuroscience, transcriptomic, General Medicine, medicine.disease, Phenotype, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], Disease Models, Animal, Crosstalk (biology), 030104 developmental biology, biology.protein, General Article, Chromosome 21, Neuroscience, 030217 neurology & neurosurgery
Abstract: Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype–phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene–gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.
Published: 2021
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17. Importing genetically altered animals: ensuring quality

Author: Guillaume Pavlovic, Edward Ryder, R. Matteoni, Marie-Christine Birling, Jan Rozman, Lydia Teboul, Ferdinando Scavizzi, Martin Fray, Lauryl M J Nutter, Marcello Raspa, Sara Wells, Petr Kasparek, J. Kopkanova, M. Massimi, V. Voikar, Lluis Montoliu, Biosciences, Neuroscience Center, French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MRC Harwell, Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), CNR - Italian National Research Council (CNR), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), The Hospital for sick children [Toronto] (SickKids), The Wellcome Trust Sanger Institute [Cambridge], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and univOAK, Archive ouverte
Subjects: EXPRESSION, media_common.quotation_subject, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, MOUSE, mouse mutant, 03 medical and health sciences, 0302 clinical medicine, Documentation, REPRODUCIBILITY, Genetics, Animals, Humans, Quality (business), 030304 developmental biology, media_common, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, disease model, 1184 Genetics, developmental biology, physiology, Reproducibility of Results, MICROBIOTA, GENE, Biological materials, Research Personnel, CRE RECOMBINASE, RODENT, MICE, Risk analysis (engineering), CELLS, RAT, 030217 neurology & neurosurgery
Abstract: The reproducibility of research using laboratory animals requires reliable management of their quality, in particular of their genetics, health and environment, all of which contribute to their phenotypes. The point at which these biological materials are transferred between researchers is particularly sensitive, as it may result in a loss of integrity of the animals and/or their documentation. Here, we describe the various aspects of laboratory animal quality that should be confirmed when sharing rodent research models. We also discuss how repositories of biological materials support the scientific community to ensure the continuity of the quality of laboratory animals. Both the concept of quality and the role of repositories themselves extend to all exchanges of biological materials and all networks that support the sharing of these reagents.
Published: 2021
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18. Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism

Author: Slimane Ait-Si-Ali, Marie Wattenhofer-Donzé, Marie-France Champy, Renaud Pourpre, Alice Lebreton, Goran Lakisic, Pascale Cossart, Morwenna Le Guillou, Hélène Bierne, Tania Sorg, Guillaume Soubigou, Emanuele Libertini, Anne C. Ferguson-Smith, Jean Feunteun, Jean-Yves Coppée, Elizabeth J. Radford, Olivia Wendling, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, French Ligue Nationale Contre le Cancer (comité régional d’Ile–de-France, LNCC RS10/75–76 and LNCC 131/12, INRA AO blanc MICA 2011, iXcore Fundation for Research, ANR-11-BSV3-0003,EPILIS,Reprogrammation épigénétique par la bactérie pathogène Listeria monocytogenes(2011), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Lebreton, Alice, BLANC - Reprogrammation épigénétique par la bactérie pathogène Listeria monocytogenes - - EPILIS2011 - ANR-11-BSV3-0003 - BLANC - VALID, Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID, Bierne, Hélène, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radford, Elizabeth [0000-0002-8336-6045], Ferguson-Smith, Anne [0000-0003-4996-9990], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Embryology, Cancer Research, Chromosomal Proteins, Non-Histone, Placenta, dna methylation, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Mice, Pregnancy, Gene expression, Medicine and Health Sciences, Small interfering RNAs, Genetics (clinical), estrogen-receptor-alpha, histone deacetylase, transcriptional repression, glycogen cells, breast-cancer, sant domain, Regulation of gene expression, Mice, Knockout, biology, Chromosome Biology, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Gene Expression Regulation, Developmental, Nuclear Proteins, Genomics, Chromatin, Precipitation Techniques, Cell biology, Nucleic acids, DNA-Binding Proteins, Histone, DNA methylation, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Epigenetics, Female, Steroids, Anatomy, DNA modification, Transcriptome Analysis, Chromatin modification, Research Article, lcsh:QH426-470, Steroid hormone receptor, Research and Analysis Methods, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Genetics, Immunoprecipitation, Animals, Humans, Non-coding RNA, Molecular Biology, Transcription factor, Ecology, Evolution, Behavior and Systematics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Reproductive System, Estrogen Receptor alpha, Biology and Life Sciences, Computational Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, DNA, Genome Analysis, Molecular biology, Placentation, Gene regulation, lcsh:Genetics, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, HEK293 Cells, biology.protein, RNA, Transcriptome, Developmental Biology, Transcription Factors
Abstract: BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases., Author Summary The importance of epigenetics in regulation and dysfunction of metabolic pathways is increasingly recognized but the underlying mechanisms and molecular actors involved remain incompletely characterized. Here, we provide evidence that the heterochromatinization factor BAHD1 cooperates with MIER proteins to assemble chromatin-repressive complexes that control a network of metabolic genes involved in placental and fetal growth and in cholesterol homeostasis.
Published: 2020
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19. Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models

Author: Valérie Nalesso, Yann Herault, Sandra Martin Lorenzo, Marie-Christine Birling, Claire Chevalier, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), and Herault, Yann
Subjects: RHOA, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Mutant, Neurodevelopment, Preclinical treatment, Intellectual disability, Chromosome Disorders, lcsh:RC346-429, Recognition memory, Exon, Mice, 0302 clinical medicine, Cognition, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Copy-number variation, ComputingMilieux_MISCELLANEOUS, Genetics, Mice, Knockout, 0303 health sciences, rho-Associated Kinases, Fasudil, Ubiquitin-Protein Ligase Complexes, Autism spectrum disorders, Phenotype, Psychiatry and Mental health, Treatment Outcome, Chromosome Deletion, Signal Transduction, Locus (genetics), [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, Mouse model, 03 medical and health sciences, Developmental Neuroscience, Memory, Memory improvement, Animals, Learning, Genetic Predisposition to Disease, KCTD13, Autistic Disorder, Molecular Biology, Alleles, Genetic Association Studies, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Copy number variation, Research, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Disease Models, Animal, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, biology.protein, rhoA GTP-Binding Protein, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16, Developmental Biology
Abstract: Background Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway. Methods Here, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. Results We found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway. Limitations The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background. Conclusion These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.
Published: 2020
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20. Human and mouse essentiality screens as a resource for disease gene discovery

Author: Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Westerberg, Henrik, Scott, R. H., Siddiq, A., Sieghart, A., Smith, K. R., Sosinsky, A., Spooner, W., Stevens, H. E., Stuckey, A., Sultana, R., Thomas, E. R. A., Konopka, Tomasz, Thompson, S. R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S. A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Hsu, Chih-Wei, Marschall, Susan, Lengger, Christoph, Maier, Holger, Seisenberger, Claudia, Bürger, Antje, Kühn, Ralf, Schick, Joel, Hörlein, Andreas, Oritz, Oskar, Giesert, Florian, Christiansen, Audrey, Beig, Joachim, Kenyon, Janet, Codner, Gemma, Fray, Martin, Johnson, Sara J, Cleak, James, Szoke-Kovacs, Zsombor, Lafont, David, Vancollie, Valerie E, McLaren, Robbie S B, Lanza, Denise G, Hughes-Hallett, Lena, Rowley, Christine, Sanderson, Emma, Galli, Antonella, Tuck, Elizabeth, Green, Angela, Tudor, Catherine, Siragher, Emma, Dabrowska, Monika, Mazzeo, Cecilia Icoresi, Beaudet, Arthur L, Griffiths, Mark, Gannon, David, Doe, Brendan, Cockle, Nicola, Kirton, Andrea, Bottomley, Joanna, Ingle, Catherine, Ryder, Edward, Gleeson, Diane, Ramirez-Solis, Ramiro, Heaney, Jason D, Birling, Marie-Christine, Pavlovic, Guillaume, Ayadi, Abdel, Hamid, Meziane, About, Ghina Bou, Champy, Marie-France, Jacobs, Hugues, Wendling, Olivia, Leblanc, Sophie, Vasseur, Laurent, Fuchs, Helmut, Chesler, Elissa J, Kumar, Vivek, White, Jacqueline K, Svenson, Karen L, Wiegand, Jean-Paul, Anderson, Laura L, Wilcox, Troy, Clark, James, Ryan, Jennifer, Denegre, James, Gailus-Durner, Valerie, Stearns, Tim, Philip, Vivek, Witmeyer, Catherine, Bates, Lindsay, Seavey, Zachary, Stanley, Pamela, Willet, Amelia, Roper, Willson, Creed, Julie, Moore, Michayla, Sorg, Tania, Dorr, Alex, Fraungruber, Pamelia, Presby, Rose, Mckay, Matthew, Nguyen-Bresinsky, Dong, Goodwin, Leslie, Urban, Rachel, Kane, Coleen, Murray, Stephen A, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Dickinson, Mary E, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Bucan, Maja, Lloyd, K C Kent, Brown, Steve D M, Parkinson, Helen, Meehan, Terrence F, Smedley, Damian, Consortium, Genomics England Research, Consortium, International Mouse Phenotyping, Ambrose, J. C., Arumugam, P., Baple, E. L., Nutter, Lauryl M J, Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Peterson, Kevin A, Devereau, A., Elgar, G., Foulger, R. E., Fowler, T., Furió-Tarí, P., Hackett, J. M., Halai, D., Hamblin, A., Henderson, S., Holman, J. E., Haselimashhadi, Hamed, Hubbard, T. J. P., Ibáñez, K., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S. E. A., Leong, I. U. S., Flenniken, Ann M, Lopez, F. J., Maleady-Crowe, F., Mason, J., McDonagh, E. M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., Odhams, C. A., Patch, C., Morgan, Hugh, Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Cacheiro, Pilar [0000-0002-6335-8208], Muñoz-Fuentes, Violeta [0000-0003-3574-546X], Nutter, Lauryl MJ [0000-0001-9619-146X], Peterson, Kevin A [0000-0001-8353-3694], Haselimashhadi, Hamed [0000-0001-7334-2421], Konopka, Tomasz [0000-0003-3042-4712], Hsu, Chih-Wei [0000-0002-9591-9567], Lanza, Denise G [0000-0001-8750-6933], Heaney, Jason D [0000-0001-8475-8828], Fuchs, Helmut [0000-0002-5143-2677], Gailus-Durner, Valerie [0000-0002-6076-0111], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Mammano, Fabio [0000-0003-3751-1691], McKerlie, Colin [0000-0002-2232-0967], Herault, Yann [0000-0001-7049-6900], de Angelis, Martin Hrabě [0000-0002-7898-2353], Lloyd, KC Kent [0000-0002-5318-4144], Smedley, Damian [0000-0002-5836-9850], Apollo - University of Cambridge Repository, Queen Mary University of London (QMUL), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, The Jackson Laboratory [Bar Harbor] (JAX), Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania, The Hospital for sick children [Toronto] (SickKids), Mount Sinai Hospital [Toronto, Canada] (MSH), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), The Wellcome Trust Sanger Institute [Cambridge], Technische Universität München = Technical University of Munich (TUM), Ludwig-Maximilians-Universität München (LMU), CNR - Italian National Research Council (CNR), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of California [Davis] (UC Davis), University of California (UC), J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A Odhams, C Patch, D Perez-Gil, D Polychronopoulos, J Pullinger, T Rahim, A Rendon, P Riesgo-Ferreiro, T Rogers, M Ryten, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki, Susan Marschall, Christoph Lengger, Holger Maier, Claudia Seisenberger, Antje Bürger, Ralf Kühn, Joel Schick, Andreas Hörlein, Oskar Oritz, Florian Giesert, Joachim Beig, Janet Kenyon, Gemma Codner, Martin Fray, Sara J Johnson, James Cleak, Zsombor Szoke-Kovacs, David Lafont, Valerie E Vancollie, Robbie S B McLaren, Lena Hughes-Hallett, Christine Rowley, Emma Sanderson, Antonella Galli, Elizabeth Tuck, Angela Green, Catherine Tudor, Emma Siragher, Monika Dabrowska, Cecilia Icoresi Mazzeo, Mark Griffiths, David Gannon, Brendan Doe, Nicola Cockle, Andrea Kirton, Joanna Bottomley, Catherine Ingle, Edward Ryder, Diane Gleeson, Ramiro Ramirez-Solis, Marie-Christine Birling, Guillaume Pavlovic, Abdel Ayadi, Meziane Hamid, Ghina Bou About, Marie-France Champy, Hugues Jacobs, Olivia Wendling, Sophie Leblanc, Laurent Vasseur, Elissa J Chesler, Vivek Kumar, Jacqueline K White, Karen L Svenson, Jean-Paul Wiegand, Laura L Anderson, Troy Wilcox, James Clark, Jennifer Ryan, James Denegre, Tim Stearns, Vivek Philip, Catherine Witmeyer, Lindsay Bates, Zachary Seavey, Pamela Stanley, Amelia Willet, Willson Roper, Julie Creed, Michayla Moore, Alex Dorr, Pamelia Fraungruber, Rose Presby, Matthew Mckay, Dong Nguyen-Bresinsky, Leslie Goodwin, Rachel Urban, Coleen Kane, Herault, Yann, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: 0301 basic medicine, Mutation rate, Cancer Research, [SDV]Life Sciences [q-bio], General Physics and Astronomy, methods [Genetic Association Studies], Disease, VARIANTS, Mice, Essential, 0302 clinical medicine, IMPC, Genetics research, Lethal allele, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Organism, ComputingMilieux_MISCELLANEOUS, Disease gene, Mice, Knockout, 0303 health sciences, Multidisciplinary, Genes, Essential, genetics [Disease], Genomics, R/BIOCONDUCTOR PACKAGE, DATABASE, UPDATE, GENOME, [SDV] Life Sciences [q-bio], Knockout mouse, Identification (biology), ddc:500, International Mouse Phenotyping Consortium, Technology Platforms, Biotechnology, Knockout, Science, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Genetic variation, Clinical genetics, Gene, Genetic Association Studies, 030304 developmental biology, Disease model, Prevention, Human Genome, General Chemistry, medicine.disease, Developmental disorder, Good Health and Well Being, 030104 developmental biology, Genomics England Research Consortium, Genes, lcsh:Q, Generic health relevance, 030217 neurology & neurosurgery, Rare disease
Abstract: The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.
Published: 2020
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21. Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny

Author: Maria Osipenko, Hamid Meziane, Binnaz Yalcin, Gabrielle Rudolf, John S. Allingham, Ekaterina L. Ivanova, Maria-Victoria Hinckelmann, Loic Broix, Johan G. Gilet, Valerie Skory, Benjamin H. Kwok, Marie-Christine Birling, Jérémie Courraud, Daria Trofimova, Nathalie Drouot, Jamel Chelly, Nadia Bahi-Buisson, Paul Voulleminot, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Queen's University [Kingston, Canada], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, EU Seventh Framework Programme FP7 under the projects GENCODYS (COLLABORATION PROJECT-2009-2.1.1-1/241995 to Ja.C.), DESIRE (grant agreement no. 602531 to Ja.C.), the French state funds through the ‘Agence Nationale de la Recherche’ under the projects ANR-15-CE16–0018-01 and the programme Investissements d’Avenir labeled (ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT to B.Y. and Ja.C.)., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), European Project: 241995,EC:FP7:HEALTH,FP7-HEALTH-2009-two-stage,GENCODYS(2010), European Project: 602531,HEALTH,FP7-HEALTH-2013-INNOVATION-1,DESIRE(2013), YALCIN, Binnaz, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Genetic and Epigenetic Networks in Cognitive Dysfunction - GENCODYS - - EC:FP7:HEALTH2010-05-01 - 2015-04-30 - 241995 - VALID, Development and Epilepsy - Strategies for Innovative Research to improve diagnosis, prevention and treatment in children with difficult to treat Epilepsy - DESIRE - - HEALTH2013-01-01 - 2018-09-30 - 602531 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Male, Microcephaly, hippocampus, mouse model, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Kinesins, Hippocampus, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, knock-in, Mice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene knockin, Genetics, medicine, Animals, Missense mutation, Molecular Biology, Genetics (clinical), 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Mutation, videomicroscopy, neuronal migration, [SDV.GEN]Life Sciences [q-bio]/Genetics, Behavior, Animal, Transition (genetics), [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, apoptosis, General Medicine, General Article Two, malformations of cortical development, medicine.disease, in utero electroporation, microtubule dynamics, Phenotype, Mice, Inbred C57BL, Repressor Proteins, cortex, Neuroscience, 030217 neurology & neurosurgery, KIF2A
Abstract: By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.
Published: 2020
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22. Universal Southern blot protocol with cold or radioactive probes for the validation of alleles obtained by homologous recombination

Author: Lauren Chessum, Sara Wells, Lydia Teboul, Adam Caulder, Nicolas Jullien, Jorik Loeffler, Marie-Christine Birling, Gemma F. Codner, Valerie Erbs, Jullien, Nicolas, Mary Lyon Centre, MRC Harwell Institute, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: 0303 health sciences, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, 030302 biochemistry & molecular biology, Genetic Vectors, Computational biology, Biology, Genome, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Blotting, Southern, Mice, Radioactivity, Gene Targeting, Animals, Allele, Homologous recombination, Homologous Recombination, Molecular Biology, Gene, Alleles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Southern blot
Abstract: The widespread availability of recombineered vectors and gene targeted embryonic stem cells from large-scale repositories facilitates the generation of mouse models for functional genetic studies. Southern blotting validates the structure of these targeted alleles produced by homologous recombination, as well as indicating any additional integrations of the vector into the genome. Traditionally this technique employs radioactively-labelled probes; however, there are many laboratories that are restricted in their use of radioactivity. Here, we present a widely applicable protocol for Southern blot analysis using cold probes and alternative procedures employing radioactive probes. Furthermore, the probes are designed to recognise standardised regions of gene-targeting cassettes and so represent universally applicable reagents for assessing allelic integrity.
Published: 2020
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23. Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration

Author: Vincent Gache, Arnaud Ferry, Fanny Pilot-Storck, Olivia Wendling, Vincent Jacquemond, Vasugi Nattarayan, Jeanne Lainé, Jocelyn Laporte, Christine Kretz, Hichem Tasfaout, Roy Combe, Josiane Hergueux, Anne Toussaint, Christos Gavriilidis, Catherine Koch, Belinda S. Cowling, Candice Kutchukian, Ivana Prokic, Laurent Tiret, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Clinique de la Souris (ICS), Biologie du système neuromusculaire - Biology of the neuromuscular system [Maisons-Alfort] (BNMS - Team 10), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), École nationale vétérinaire d'Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Gestionnaire, HAL Sorbonne Université 5, BLANC - Mécano-sensation et mécano-stabilisation au cours de la morphogenèse embryonnaire - - SenStable2011 - ANR-11-BSV2-0023 - BLANC - VALID, ANR-11-BSV2-0023,SenStable,Mécano-sensation et mécano-stabilisation au cours de la morphogenèse embryonnaire(2011), and Université de Lyon
Subjects: XLMTM, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, lcsh:Medicine, Medicine (miscellaneous), Muscle Development, centronuclear myopathy, SH3 domain, Myoblast fusion, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), myoblast fusion, Protein Isoforms, myotubular myopathy, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, 0303 health sciences, triad, Homozygote, Exons, Cell biology, medicine.anatomical_structure, Organ Specificity, Knockout mouse, Intracellular, Research Article, lcsh:RB1-214, Gene isoform, Neuroscience (miscellaneous), Nerve Tissue Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, dynamin, lcsh:Pathology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Regeneration, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Centronuclear myopathy, Muscle, Skeletal, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Dynamin, myotonic dystrophy, Tumor Suppressor Proteins, Regeneration (biology), animal model, lcsh:R, Skeletal muscle, Feeding Behavior, medicine.disease, Survival Analysis, Mice, Inbred C57BL, Animals, Newborn, BAR domain, 030217 neurology & neurosurgery
Abstract: Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects., Summary: The BIN1 gene, mutated in centronuclear myopathies, expresses ubiquitous and muscle-specific isoforms. It is shown here that ubiquitous isoforms are necessary for muscle development, whereas muscle-specific isoforms fine-tune muscle regeneration.
Published: 2020
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24. BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice

Author: Laurent Naudon, Hugo Varet, Yann Herault, Renaud Pourpre, Luc Jouneau, Mohammed Selloum, Goran Lakisic, Olivia Wendling, Jean-Yves Coppée, Hélène Bierne, Hamid Meziane, Rachel Legendre, Caroline Proux, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), MICA grant, Ligue nationale contre le cancer, ANR (ANR-10-IDEX-0002-02,ANR-10-LABX-0030-INRT,ANR-10-INBS-07 PHENOMIN), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Reflex, Startle, Chromosomal Proteins, Non-Histone, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Social Sciences, Histone Deacetylase 2, Histone Deacetylase 1, Anxiety, Hippocampal formation, Biochemistry, Mice, 0302 clinical medicine, Gene expression, Medicine and Health Sciences, Psychology, ComputingMilieux_MISCELLANEOUS, Mammals, Mice, Knockout, Regulation of gene expression, Neuronal Death, Multidisciplinary, Animal Behavior, Cell Death, phenotypes, Eukaryota, Brain, Animal Models, Genomics, Phenotype, Chromatin, Cell biology, Experimental Organism Systems, Cell Processes, Vertebrates, Knockout mouse, Medicine, Anatomy, Haploinsufficiency, Transcriptome Analysis, Research Article, Science, Mouse Models, Biology, Research and Analysis Methods, Rodents, male mice, 03 medical and health sciences, Model Organisms, DNA-binding proteins, Genetics, Animals, Humans, Gene, Behavior, [SDV.GEN]Life Sciences [q-bio]/Genetics, Sequence Analysis, RNA, Hippocampal Formation, Organisms, Biology and Life Sciences, Computational Biology, Proteins, Cell Biology, Genome Analysis, HDAC1, haploinsufficiency, 030104 developmental biology, Gene Expression Regulation, Amniotes, Animal Studies, Zoology, 030217 neurology & neurosurgery
Abstract: International audience; BAHD1 is a heterochomatinization factor recently described as a component of a multiprotein complex associated with histone deacetylases HDAC1/2. The physiological and patho-physiological functions of BAHD1 are not yet well characterized. Here, we examined the consequences of BAHD1 deficiency in the brains of male mice. While Bahd1 knockout mice had no detectable defects in brain anatomy, RNA sequencing profiling revealed about 2500 deregulated genes in Bahd1-/- brains compared to Bahd1+/+ brains. A majority of these genes were involved in nervous system development and function, behavior, metabolism and immunity. Exploration of the Allen Brain Atlas and Dropviz databases, assessing gene expression in the brain, revealed that expression of the Bahd1 gene was limited to a few territories and cell subtypes, particularly in the hippocampal formation, the isocortex and the olfactory regions. The effect of partial BAHD1 deficiency on behavior was then evaluated on Bahd1 heterozygous male mice, which have no lethal or metabolic phenotypes. Bahd1+/- mice showed anxiety-like behavior and reduced prepulse inhibition (PPI) of the startle response. Altogether, these results suggest that BAHD1 plays a role in chromatin-dependent gene regulation in a subset of brain cells and support recent evidence linking genetic alteration of BAHD1 to psychiatric disorders in a human patient.
Published: 2020
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25. Oestrogen receptor α AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium

Author: Cagnet, Stéphanie, Ataca, Dalya, Sflomos, George, Aouad, Patrick, Schuepbach-Mallepell, Sonia, Hugues, Henry, Krust, Andrée, Ayyanan, Ayyakkannu, Scabia, Valentina, Brisken, Cathrin, Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), and univOAK, Archive ouverte
Subjects: Science, morphogenesis, Endocrine System, Article, Epithelium, stem-cells, Structure-Activity Relationship, progesterone-receptor, Mammary Glands, Animal, Protein Domains, Pregnancy, Animals, Cell Proliferation, Endocrine System/metabolism, Epithelial Cells/cytology, Epithelial Cells/metabolism, Epithelium/metabolism, Estrogen Receptor alpha/chemistry, Estrogen Receptor alpha/genetics, Estrogen Receptor alpha/metabolism, Female, Gene Expression Regulation, Mammary Glands, Animal/growth & development, Mammary Glands, Animal/metabolism, Mice, Inbred C57BL, Phenotype, RNA, Messenger/genetics, RNA, Messenger/metabolism, Steroids/metabolism, expression, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, transcriptional activation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, lcsh:Science, breast-cancer, mouse, single, er-alpha, Estrogen Receptor alpha, Epithelial Cells, gland development, Steroids, lcsh:Q, hormones, hormone substitutes, and hormone antagonists
Abstract: Oestrogen receptor α (ERα) is a transcription factor with ligand-independent and ligand-dependent activation functions (AF)-1 and -2. Oestrogens control postnatal mammary gland development acting on a subset of mammary epithelial cells (MECs), termed sensor cells, which are ERα-positive by immunohistochemistry (IHC) and secrete paracrine factors, which stimulate ERα-negative responder cells. Here we show that deletion of AF-1 or AF-2 blocks pubertal ductal growth and subsequent development because both are required for expression of essential paracrine mediators. Thirty percent of the luminal cells are ERα-negative by IHC but express Esr1 transcripts. This low level ERα expression through AF-2 is essential for cell expansion during puberty and growth-inhibitory during pregnancy. Cell-intrinsic ERα is not required for cell proliferation nor for secretory differentiation but controls transcript levels of cell motility and cell adhesion genes and a stem cell and epithelial mesenchymal transition (EMT) signature identifying ERα as a key regulator of mammary epithelial cell plasticity., Oestrogen receptors α (ERα) are expressed in a subset of mammary epithelial cells. Here, the authors identify cells with low-ERα protein levels and show that distinct cell populations have distinct requirements for the AF1 and AF2 domains of the ERα, and ERα acts in a biphasic manner dependent on developmental stage.
Published: 2018
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26. TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis

Author: Nathalie Drouot, Patrick Nusbaum, William Magnant, Binnaz Yalcin, Arnaud Duchon, Loic Broix, Jamel Chelly, Valerie Skory, Stephan C. Collins, Maria-Victoria Hinckelmann, Vadym Sulimenko, Yann Herault, Marie-Christine Birling, Juliette D. Godin, Guillaume Pavlovic, Pavel Dráber, Karen Runge, Laure Asselin, Ekaterina L. Ivanova, Gabrielle Rudolf, Peggy Tilly, Alexandre Vincent, Johan G. Gilet, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biology of Cytoskeleton, Institute of Molecular Genetics, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), UFR Sciences de la Vie, de la Terre et de l'Environnement (Université de Bourgogne) (UFR SVTE), Université de Bourgogne (UB), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Les Hôpitaux Universitaires de Strasbourg (HUS), and Herault, Yann
Subjects: Male, 0301 basic medicine, Intravital Microscopy, TUBG1, General Physics and Astronomy, [SDV.GEN] Life Sciences [q-bio]/Genetics, 02 engineering and technology, medicine.disease_cause, Microtubules, Mice, Epilepsy, Cell Movement, Tubulin, Missense mutation, Gene Knock-In Techniques, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, Neurons, Mutation, Microscopy, Confocal, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Behavior, Animal, Electroporation, Neurogenesis, 021001 nanoscience & nanotechnology, Malformations of Cortical Development, Female, 0210 nano-technology, Science, Transgene, Mutation, Missense, Mice, Transgenic, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Developmental biology, medicine, Animals, Humans, Genetic Predisposition to Disease, Centrosome, [SDV.GEN]Life Sciences [q-bio]/Genetics, Disease model, Development of the nervous system, General Chemistry, Fibroblasts, Embryo, Mammalian, medicine.disease, Disease Models, Animal, Microscopy, Electron, 030104 developmental biology, lcsh:Q, Neuroscience, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, HeLa Cells
Abstract: De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors’ proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations., New mutations and genes associated with malformations of cortical development keep being identified, yet there is little known about the underlying cellular mechanisms controlling these impairments. Here, authors generate and characterize a heterozygous TUBG1 knock-in mouse model bearing one of these known mutations and show that TUBG1 mutation leads to the miss-positioning of neurons in the cortical wall due to migration, because of defective microtubules dynamics, and not proliferation defects during corticogenesis.
Published: 2019
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27. Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse

Author: Ung, D., Iacono, G, Méziane, H, Blanchard, E., Papon, M-A, Selten, M, van Rhijn, J-R, Montjean, R, Rucci, J, Martin, Stéphane, Fleet, A, Birling, M-C, Marouillat, S, Roepman, R, Selloum, M, Lux, A., Thépault, R-A, Hamel, P, Mittal, K, Vincent, J., Dorseuil, O, Stunnenberg, H, Billuart, P, Nadif Kasri, N, Hérault, Y., Laumonnier, F, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Radboud university [Nijmegen], Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Donders Institute for Brain, Cognition and Behaviour, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), University of Toronto, Radboud University Medical Center [Nijmegen], Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Martin, Stephane, Radboud University [Nijmegen], and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Hippocampus, Synaptic Transmission, Mice, [SCCO]Cognitive science, Cognition, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Basic Helix-Loop-Helix Transcription Factors, Animals, Cognitive Dysfunction, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Neurons, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Membrane Proteins, [SCCO] Cognitive science, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Synapses, Original Article, Disks Large Homolog 4 Protein, Guanylate Kinases, Signal Transduction
Abstract: Contains fulltext : 193089.pdf (Publisher’s version ) (Open Access) Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1(-/y)) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.
Published: 2018
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28. Modeling Down syndrome in animals from the early stage to the 4.0 models and next

Author: Del Mar Muñ Iz Moreno, Maria, Brault, Veronique, Hérault, Yann, Mar, Maria, Moreno, Muñiz, Brault, Véronique, Birling, Marie-Christine, Pavlovic, Guillaume, Herault, Yann, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Recherche Agronomique (INRA), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Le génie génétique et la conception [Illkirch-Graffenstaden], BRAULT, Véronique, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Transchromosomic, Down syndrome, Computational biology, Disease, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Neurobiology of disease, Genome, Nature versus nurture, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, CRISPR, Homologous gene, Chromosomal engineering, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Behavior and cognition, medicine.disease, 3. Good health, Animal models, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Transgenesis, Chromosome 21, 030217 neurology & neurosurgery
Abstract: International audience; The genotype-phenotype relationship and the physiopathology of Down Syndrome (DS) have been explored in the last 20 years with more and more relevant mouse models. From the early age of transgenesis to the new CRISPR/CAS9-derived chromosomal engineering and the transchromosomic technologies, mouse models have been key to identify homolo-gous genes or entire regions homologous to the human chromosome 21 that are necessary or sufficient to induce DS features, to investigate the complexity of the genetic interactions that are involved in DS and to explore therapeutic strategies. In this review we report the new developments made, how genomic data and new genetic tools have deeply changed our way of making models, extended our panel of animal models, and increased our understanding of the neurobiology of the disease. But even if we have made an incredible progress which promises to make DS a curable condition, we are facing new research challenges to nurture our knowledge of DS pathophysiology as a neurodevelopmental disorder with many comorbidities during ageing.
Published: 2019
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29. Optimizing PCR for Mouse Genotyping: Recommendations for Reliable, Rapid, Cost Effective, Robust and Adaptable to High‐Throughput Genotyping Protocol for Any Type of Mutation

Author: Sylvie Jacquot, Françoise Piguet, Guillaume Pavlovic, Yann Herault, Nathalie Chartoire, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), and Herault, Yann
Subjects: Genotyping Techniques, [SDV.BA] Life Sciences [q-bio]/Animal biology, Computer science, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Computational biology, Polymerase Chain Reaction, Genome, law.invention, Mice, 03 medical and health sciences, 0302 clinical medicine, law, Animals, Sequence variation, Genotyping, ComputingMilieux_MISCELLANEOUS, Polymerase chain reaction, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, [SDV.BA]Life Sciences [q-bio]/Animal biology, High-Throughput Nucleotide Sequencing, Reproducibility of Results, General Medicine, Tissue sampling, [SDV] Life Sciences [q-bio], Mutation, High throughput genotyping, 030217 neurology & neurosurgery, Animal facility
Abstract: Genotyping consists of searching for a DNA sequence variation localized at a well-defined locus in the genome. It is an essential step in animal research because it allows the identification of animals that will be bred to generate and maintain a colony, euthanized to control the available space in the animal facility, or used in experiment protocols. Here we describe polymerase chain reaction (PCR) genotyping protocols for fast, sensitive, easy, and cost-effective characterization of mouse genotype. We discuss optimization of parameters to improve the reliability of each assay and propose recommendations for enhancing reproducibility and reducing the occurrence of inconclusive genotyping. All steps required for efficient genotyping are presented: tissue collection; sample verification and direct DNA lysis; establishment of a robust genotyping strategy with reliable, rapid, and cost-effective assays; and finally, transition to high-throughput automatized PCR, including mix miniaturization and automation. © 2019 The Authors. Basic Protocol 1: Tissue sampling methods and procedure Basic Protocol 2: Sample verification and DNA lysis Basic Protocol 3: Design of a genotyping strategy Basic Protocol 4: Moving to high-throughput genotyping.
Published: 2019
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30. Meiosis Initiates In The Fetal Ovary Of Mice Lacking All Retinoic Acid Receptor Isotypes

Author: Muriel Klopfenstein, Betty Féret, Marius Teletin, Violaine Alunni, Diana Condrea, Nadège Vernet, Manuel Mark, Norbert B. Ghyselinck, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and GHYSELINCK, Norbert B.
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], organic chemicals, Zygotene Stage, Retinoic acid, Gene targeting, Ovary, Biology, biological factors, Cell biology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Meiotic Prophase I, Retinoic acid receptor, chemistry.chemical_compound, 0302 clinical medicine, medicine.anatomical_structure, Meiosis, chemistry, embryonic structures, medicine, neoplasms, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Gametes are generated through a specialized cell differentiation process, meiosis which, in most mammals, is initiated in ovaries during fetal life. It is widely admitted that all-transretinoic acid (ATRA) is the molecular signal triggering meiosis initiation in mouse female germ cells, but a genetic approach in which ATRA synthesis is impaired disputes this proposal. In the present study, we investigated the contribution of endogenous ATRA to meiosis by analyzing fetuses lacking all RARs ubiquitously, obtained through a tamoxifen-inducible cre recombinase-mediated gene targeting approach. Efficient ablation of RAR-coding genes was assessed by the multiple congenital abnormalities displayed by the mutant fetuses. Unexpectedly, their germ cells robustly expressed STRA8, REC8, SYCP1 and SYCP3, showing that RAR are actually dispensable up to the zygotene stage of meiotic prophase I. Thus our study goes against the current model according to which meiosis is triggered by endogenous ATRA in the developing ovary and revives the identification of the meiosis-preventing substance synthesized by CYP26B1 in the fetal testis.
Published: 2019
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31. Ultrasound-Guided Approaches to Improve Orthotopic Mouse Xenograft Models for Hepatocellular Carcinoma

Author: Yann Herault, Emilie Thiebault, Thomas F. Baumert, Ghina Bou About, Tania Sorg, Laurent Monassier, Hugues Jacobs, Eric Robinet, Marie Wattenhofer-Donzé, Alain Guimond, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurobiologie et pharmacologie cardiovasculaire (LNPCV), Université de Strasbourg (UNISTRA), Laboratoire de pharmacologie et toxicologie neurocardiovasculaire (LPTNC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut de Chirurgie guidée par l'Image, and univOAK, Archive ouverte
Subjects: Cirrhosis, Huh-7, Sciences du Vivant [q-bio]/Cancer, Heterologous/instrumentation/*methods, Mice, 0302 clinical medicine, Liver Neoplasms, Experimental, Ultrasonics, Stage (cooking), 0303 health sciences, Sciences du Vivant [q-bio]/Ingénierie biomédicale, Liver Neoplasms, Liver Neoplasms/therapy, Sciences du Vivant [q-bio]/Biotechnologies, General Medicine, 3. Good health, Drug development, Hepatocellular carcinoma, Heterografts, medicine.drug, Carcinoma, Hepatocellular, Experimental/*therapy, Transplantation, Heterologous, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ultrasonics/instrumentation/*methods, Hepatocellular/therapy, doxorubicin, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, echo-guided injection, medicine, Carcinoma, Distribution (pharmacology), Animals, Doxorubicin, orthotopic, 030304 developmental biology, Heterografts/*physiology, Transplantation, business.industry, echography, medicine.disease, digestive system diseases, hepatocarcinoma, Cancer research, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. While curative approaches for early stage HCC exist, effective treatment options for advanced HCC are lacking. Furthermore, there are no efficient chemopreventive strategies to limit HCC development once cirrhosis is established. One challenge for drug development is unsatisfactory animal models. In this article, we describe an orthotopic xenograft mouse model of human liver cancer cell lines through image-guided injection into the liver. This technique provides a less invasive yet highly efficient approach to engraft human HCC into mouse liver. Similarly, image-guided injections are used to deliver chemotherapeutics locally, enabling reduction in potential systemic adverse effects, while reducing the required dose for a therapeutic effect. In summary, this image-guided strategy provides a novel and convenient approach to improve current HCC mouse models. (c) 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Published: 2019
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32. HENA, heterogeneous network-based data set for Alzheimer's disease

Author: Elena Sügis, Rachel Daudin, Vincent Collura, Yann Herault, Valerie Hindie, Yann Loe-Mie, Jean-Charles Lambert, Michel Simonneau, Jérôme Dauvillier, Priit Adler, Hedi Peterson, Thomas Moncion, Henning Hermjakob, Anna Leontjeva, Jean-Christophe Rain, Tal Pupko, Jaak Vilo, Ioannis Xenarios, Quretec Ltd., Institute of Computer Science [University of Tartu, Estonie], University of Tartu, Vital-IT, Swiss Institute of Bioinformatics [Genève] (SIB), Data61 [Canberra] (CSIRO), Australian National University (ANU)-Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Hybrigenics [Paris], Hybrigenics, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Aimé Cotton (LAC), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Cachan (ENS Cachan), Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrate Development, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Tel Aviv University [Tel Aviv], Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), We would like to acknowledge the funding support from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 305299. We also give thanks to the Estonian Research Council grants (PSG59, IUT34-4), the European Regional Development Fund for CoE of Estonian ICT research EXCITE project., Additionally, we thank Yuriy Tyshetskiy and Kevin Jung who provided insight and expertise that greatly assisted the development of the case study, and Ivan Kuzmin for assisting in solving non-trivial technical issues., Herault, Yann, École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrates Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Tel Aviv University (TAU), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), and Centre de Psychiatrie et Neurosciences (U894)
Subjects: Statistics and Probability, Data Descriptor, 010504 meteorology & atmospheric sciences, Computer science, Gene Expression, Context (language use), [SDV.GEN] Life Sciences [q-bio]/Genetics, Library and Information Sciences, 01 natural sciences, Education, 03 medical and health sciences, Deep Learning, Alzheimer Disease, Two-Hybrid System Techniques, Protein Interaction Mapping, medicine, Dementia, Humans, lcsh:Science, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Biological data, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], business.industry, Deep learning, Epistasis, Genetic, Scientific data, Alzheimer's disease, medicine.disease, Data science, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Regulatory networks, 3. Good health, Computer Science Applications, Metadata, Data set, Graph (abstract data type), lcsh:Q, Data integration, Artificial intelligence, Statistics, Probability and Uncertainty, business, Heterogeneous network, Information Systems
Abstract: Alzheimer’s disease and other types of dementia are the top cause for disabilities in later life and various types of experiments have been performed to understand the underlying mechanisms of the disease with the aim of coming up with potential drug targets. These experiments have been carried out by scientists working in different domains such as proteomics, molecular biology, clinical diagnostics and genomics. The results of such experiments are stored in the databases designed for collecting data of similar types. However, in order to get a systematic view of the disease from these independent but complementary data sets, it is necessary to combine them. In this study we describe a heterogeneous network-based data set for Alzheimer’s disease (HENA). Additionally, we demonstrate the application of state-of-the-art graph convolutional networks, i.e. deep learning methods for the analysis of such large heterogeneous biological data sets. We expect HENA to allow scientists to explore and analyze their own results in the broader context of Alzheimer’s disease research., Design Type(s)data integration objective • disease analysis objectiveMeasurement Type(s)Alzheimer’s diseaseTechnology Type(s)digital curationFactor Type(s)Sample Characteristic(s)Homo sapiens • brain Machine-accessible metadata file describing the reported data (ISA-Tab format)
Published: 2019
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33. 214th ENMC International Workshop: Establishing an international consortium for gene discovery and clinical research for Congenital Muscle Disease, Heemskerk, the Netherlands, 6-18 October 2015

Author: Sandra Donkervoort, James J. Dowling, Jocelyn Laporte, Daniel MacArthur, Carsten G. Bönnemann, Alan Beggs, Gisele Bonne, Carsten Bönnemann, James Dowling, Victor Dubowitz, Michael Goldberg, Morton Goldberg, Yann Herault, Mert Karakaya, Anne Lennox, Eduardo Malfatti, Katherine Mathews, Marina Mora, Ichizo Nishino, Emily Oates, Anne Rutkowski, Melanie Spring, Nicol Voermans, Jodi Warman, Tobias Willer, Hui Xiong, Irina Zaharieva, Edmar Zanoteli, Boston Children's Hospital, Thérapie des maladies du muscle strié, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Biology and Genetics, Cornell University [New York], Wilmer Eye Institute, Johns Hopkins University School of Medicine, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Unité UMR_S956, Centre de Recherche en Myologie, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Clinical research, Muscle disease, Neurology, Family medicine, Pediatrics, Perinatology and Child Health, Medicine, Neurology (clinical), business, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Genetics (clinical), Gene Discovery, 030304 developmental biology
Abstract: International audience
Published: 2019
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34. The neuroanatomy of Eml1 knockout mice, a model of subcortical heterotopia

Author: Mohammed Selloum, Binnaz Yalcin, Ana Uzquiano, Stephan C. Collins, Maria Osipenko, Marie-Christine Birling, Marion Gaborit, Fiona Francis, Olivia Wendling, ProdInra, Migration, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Cortex development and pathology (U1270), Institut du Fer à Moulin, Institut Clinique de la Souris, French Agence National de la Recherche (ANR), INSERM, Université Pierre et Marie Curie, Ecole des Neurosciences Paris Ile de France, Fondation Maladies Rares/Phenomin (project IR4995), CNRS, European Cooperation on Science and Technology (COST Action CA16118), JTC 2015 Neurodevelopmental Disorders, Fondation de France, European Union (EU‐ HEALTH‐2013, DESIRE, No 60253), BioPsy Labex, Fondation Bettencourt Schueller., Institut Clinique de la Souris (ICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), U964, and Gestionnaire, Hal Sorbonne Université
Subjects: 0301 basic medicine, Male, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], heterotopia, Histology, [SDV.BA] Life Sciences [q-bio]/Animal biology, Classical Lissencephalies and Subcortical Band Heterotopias, Biology, Corpus callosum, 03 medical and health sciences, 0302 clinical medicine, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Progenitor cell, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Mice, Knockout, [SDV.BA]Life Sciences [q-bio]/Animal biology, Brain, Heterozygote advantage, Cell Biology, Original Articles, mouse model of developmental disorders, medicine.disease, cortical malformations, Corticogenesis, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Heterotopia (medicine), Cerebral cortex, Knockout mouse, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Neuroscience, Microtubule-Associated Proteins, 030217 neurology & neurosurgery, Developmental Biology, Neuroanatomy
Abstract: Symposium issue: Human Cortex Developmentidentifiant wos: 000482426800014; International audience; The cerebral cortex is a highly organized structure responsible for advanced cognitive functions. Its development relies on a series of steps including neural progenitor cell proliferation, neuronal migration, axonal outgrowth and brain wiring. Disruption of these steps leads to cortical malformations, often associated with intellectual disability and epilepsy. We have generated a new resource to shed further light on subcortical heterotopia, a malformation characterized by abnormal neuronal position. We describe here the generation and characterization of a knockout (KO) mouse model for Eml1, a microtubule-associated protein showing mutations in human ribbon-like subcortical heterotopia. As previously reported for a spontaneous mouse mutant showing a mutation in Eml1, we observe severe cortical heterotopia in the KO. We also observe abnormal progenitor cells in early corticogenesis, likely to be the origin of the defects. EML1 KO mice on the C57BL/6N genetic background also appear to present a wider phenotype than the original mouse mutant, showing additional brain anomalies, such as corpus callosum abnormalities. We compare the anatomy of male and female mice and also study heterozygote animals. This new resource will help unravel roles for Eml1 in brain development and tissue architecture, as well as the mechanisms leading to severe subcortical heterotopia.
Published: 2019
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35. Cbs overdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically with Dyrk1a

Author: Damien Marechal, Yann Herault, Patricia Lopes Pereira, Nadège Loaëc, Alice Leon, Gaëlle Friocourt, Dehren Martin, Marc Blondel, Marie-Christine Birling, Véronique Brault, BRAULT, Véronique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inserm UMR 1078, Université de Bretagne Occidentale, Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), ManRos Therapeutics, Institut Clinique de la Souris (ICS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, 3B Rue de la Férollerie 45071 Orléans, France, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Proteomics, DYRK1A, Proteome, Gene Dosage, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, 0302 clinical medicine, Cognition, Genetics (clinical), Neurons, 0303 health sciences, Behavior, Animal, Kinase, General Medicine, Protein-Tyrosine Kinases, Phenotype, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Locomotion, inorganic chemicals, congenital, hereditary, and neonatal diseases and abnormalities, Down syndrome, Cell projection morphogenesis, Cystathionine beta-Synthase, Mice, Transgenic, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Protein Serine-Threonine Kinases, 03 medical and health sciences, Memory, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Genetics, medicine, Animals, Humans, Molecular Biology, Gene, Recognition memory, 030304 developmental biology, [SCCO.NEUR]Cognitive science/Neuroscience, organic chemicals, [SCCO.NEUR] Cognitive science/Neuroscience, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Epistasis, Genetic, medicine.disease, Actin cytoskeleton, Disease Models, Animal, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Down Syndrome, Chromosome 21, Neuroscience, 030217 neurology & neurosurgery
Abstract: Identifying dosage sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) show cognitive phenotype and needs to be investigated to identify the main genetic driver. Here, we report that, in the Dp1Yah mice, 3 copies of the Cystathionine-beta-synthase gene (Cbs)are necessary to observe a deficit in the novel object recognition (NOR) paradigm. Moreover, the overexpression ofCbsalone is sufficient to induce NOR deficit. Accordingly targeting the overexpression of human CBS, specifically in Camk2a-expressing neurons, leads to impaired objects discrimination. Altogether this shows thatCbsoverdosage is involved in DS learning and memory phenotypes. In order to go further, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast. Pharmacological intervention in the Tg(CBS) with one selected compound restored memory in the novel object recognition. In addition, using a genetic approach, we demonstrated an epistatic interaction betweenCbsandDyrk1a, another human chromosome 21 gene encoding the dual-specificity tyrosine phosphorylation-regulated kinase 1a and an already known target for DS therapeutic intervention. Further analysis using proteomic approaches highlighted several pathways, including synaptic transmission, cell projection morphogenesis, and actin cytoskeleton, that are affected by DYRK1A and CBS overexpression. Overall we demonstrated that CBS overdosage underpins the DS-related recognition memory deficit and that bothCBSandDYRK1Ainteract to control accurate memory processes in DS. In addition, our study establishes CBS as an intervention point for treating intellectual deficiencies linked to DS.SIGNIFICANT STATEMENTHere, we investigated a region homologous to Hsa21 and located on mouse chromosome 17. We demonstrated using three independent genetic approaches that the overdosage of the Cystathionine-beta-synthase gene (Cbs) gene, encoded in the segment, is necessary and sufficient to induce deficit in novel object recognition (NR).In addition, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast and in mouse transgenic lines. Then we analyzed the relation between Cbs overdosage and the consequence of DYRK1a overexpression, a main driver of another region homologous to Hsa21 and we demonstrated that an epistatic interaction exist betweenCbsandDyrk1aaffecting different pathways, including synaptic transmission, cell projection morphogenesis, and actin cytoskeleton.
Published: 2018
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36. Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice

Author: Claudine Ebel, Anne-Marie Knapp, Virginia Delgado, Isabelle André-Schmutz, Anne-Sophie Korganow, Pauline Soulas-Sprauel, Delphine Bouis, Delphine Lamon, Nadia Jeremiah, Florent Arbogast, Peggy Kirstetter, Alexandre Belot, Thierry Martin, Frédéric Rieux-Laucat, Yanick J. Crow, Hugues Jacobs, Sophie Jung, CCSD, Accord Elsevier, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Clinique de la Souris (ICS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Edinburgh, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, stimulator of interferon genes, [SDV]Life Sciences [q-bio], T-Lymphocytes, Immunology, Receptor, Interferon alpha-beta, Biology, Natural killer cell, 03 medical and health sciences, Mice, 0302 clinical medicine, Interferon, Agammaglobulinemia, Sciences du Vivant [q-bio]/Biologie cellulaire, medicine, Immunology and Allergy, Animals, Humans, Sciences du Vivant [q-bio]/Immunologie, Inflammation, Mice, Knockout, Severe combined immunodeficiency, B-Lymphocytes, Interferon-stimulated gene, Wild type, Membrane Proteins, Cell Differentiation, V154M, medicine.disease, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Killer Cells, Natural, Mice, Inbred C57BL, Sting, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Stimulator of interferon genes, Knockout mouse, Interferon Type I, Mutation, type I interferon, Severe Combined Immunodeficiency, 030215 immunology, medicine.drug
Abstract: International audience; Background: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts.Objective: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system.Methods: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded.Results: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency.Conclusions: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.
Published: 2017
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37. Prevalence of sexual dimorphism in mammalian phenotypic traits

Author: Damian Smedley, Colin McKerlie, Xiang Gao, Henrik Westerberg, Simon Greenaway, Monica J. Justice, Hiroshi Masuya, Elissa J. Chesler, Robert E. Braun, Mary E. Dickinson, Shay Yaacoby, Stephen A. Murray, Karen L. Svenson, Jeremy Mason, Martin Hrabé de Angelis, Luis Santos, Tania Sorg, Christopher J. Lelliott, Sara Wells, Ann M. Flenniken, Ruth Heller, Ann-Marie Mallon, Lynette Bower, Karen P. Steel, Helen Parkinson, Judith E. Mank, Arthur L. Beaudet, Kevin C K Lloyd, Richard Mott, Yann Herault, Yoav Benjamini, Jacqueline K. White, Steve D.M. Brown, Shiying Guo, John R. Seavitt, Helmut Fuchs, Natalja Kurbatova, Anneliese O. Speak, Natasha A. Karp, Ramiro Ramirez-Solis, Terrence F. Meehan, David B. West, Shigeharu Wakana, The Wellcome Trust Sanger Institute [Cambridge], AstraZeneca [Cambridge, UK], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Baylor College of Medicine (BCM), Baylor University, Tel Aviv University (TAU), University of California [Davis] (UC Davis), University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Technische Universität München = Technical University of Munich (TUM), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Nanjing University (NJU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), The Hospital for sick children [Toronto] (SickKids), University College of London [London] (UCL), RIKEN BioResource Research Center [Tsukuba, Japan] (RIKEN BRC), Queen Mary University of London (QMUL), King‘s College London, Children's Hospital Oakland Research Institute (CHORI), International Mouse Phenotyping Consortium: Yuichi Obata, Tomohiro Suzuki, Masaru Tamura, Hideki Kaneda, Tamio Furuse, Kimio Kobayashi, Ikuo Miura, Ikuko Yamada, Nobuhiko Tanaka, Atsushi Yoshiki, Shinya Ayabe, David A Clary, Heather A Tolentino, Michael A Schuchbauer, Todd Tolentino, Joseph Anthony Aprile, Sheryl M Pedroia, Lois Kelsey, Igor Vukobradovic, Zorana Berberovic, Celeste Owen, Dawei Qu, Ruolin Guo, Susan Newbigging, Lily Morikawa, Napoleon Law, Xueyuan Shang, Patricia Feugas, Yanchun Wang, Mohammad Eskandarian, Yingchun Zhu, Lauryl M J Nutter, Patricia Penton, Valerie Laurin, Shannon Clarke, Qing Lan, Khondoker Sohel, David Miller, Greg Clark, Jane Hunter, Jorge Cabezas, Mohammed Bubshait, Tracy Carroll, Sandra Tondat, Suzanne MacMaster, Monica Pereira, Marina Gertsenstein, Ozge Danisment, Elsa Jacob, Amie Creighton, Gillian Sleep, James Clark, Lydia Teboul, Martin Fray, Adam Caulder, Jorik Loeffler, Gemma Codner, James Cleak, Sara Johnson, Zsombor Szoke-Kovacs, Adam Radage, Marina Maritati, Joffrey Mianne, Wendy Gardiner, Susan Allen, Heather Cater, Michelle Stewart, Piia Keskivali-Bond, Caroline Sinclair, Ellen Brown, Brendan Doe, Hannah Wardle-Jones, Evelyn Grau, Nicola Griggs, Mike Woods, Helen Kundi, Mark N D Griffiths, Christian Kipp, David G Melvin, Navis P S Raj, Simon A Holroyd, David J Gannon, Rafael Alcantara, Antonella Galli, Yvette E Hooks, Catherine L Tudor, Angela L Green, Fiona L Kussy, Elizabeth J Tuck, Emma J Siragher, Simon A Maguire, David T Lafont, Valerie E Vancollie, Selina A Pearson, Amy S Gates, Mark Sanderson, Carl Shannon, Lauren F E Anthony, Maksymilian T Sumowski, Robbie S B McLaren, Agnieszka Swiatkowska, Christopher M Isherwood, Emma L Cambridge, Heather M Wilson, Susana S Caetano, Cecilia Icoresi Mazzeo, Monika H Dabrowska, Charlotte Lillistone, Jeanne Estabel, Anna Karin B Maguire, Laura-Anne Roberson, Guillaume Pavlovic, Marie-Christine Birling, Wattenhofer-Donze Marie, Sylvie Jacquot, Abdel Ayadi, Dalila Ali-Hadji, Philippe Charles, Philippe André, Elise Le Marchand, Amal El Amri, Laurent Vasseur, Antonio Aguilar-Pimentel, Lore Becker, Irina Treise, Kristin Moreth, Tobias Stoeger, Oana V Amarie, Frauke Neff, Wolfgang Wurst, Raffi Bekeredjian, Markus Ollert, Thomas Klopstock, Julia Calzada-Wack, Susan Marschall, Robert Brommage, Ralph Steinkamp, Christoph Lengger, Manuela A Östereicher, Holger Maier, Claudia Stoeger, Stefanie Leuchtenberger, AliÖ Yildrim, Lillian Garrett, Sabine M Hölter, Annemarie Zimprich, Claudia Seisenberger, Antje Bürger, Jochen Graw, Oliver Eickelberg, Andreas Zimmer, Eckhard Wolf, Dirk H Busch, Martin Klingenspor, Carsten Schmidt-Weber, Valérie Gailus-Durner, Johannes Beckers, Birgit Rathkolb, Jan Rozman, univOAK, Archive ouverte, Mason, Jeremy [0000-0002-2796-5123], Chesler, Elissa J [0000-0002-5642-5062], Angelis, Martin Hrabe de [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Lelliott, Christopher J [0000-0001-8087-4530], McKerlie, Colin [0000-0002-2232-0967], Wakana, Shigeharu [0000-0001-8532-0924], Yaacoby, Shay [0000-0002-2583-4170], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Genotype, Science, Mutant, General Physics and Astronomy, [SDV.GEN] Life Sciences [q-bio]/Genetics, Quantitative trait locus, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, Quantitative Trait, Quantitative Trait, Heritable, Genetics, Animals, Modifier, Gene, Heritable, Mammals, Sex Characteristics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Genes, Modifier, Body Weight, General Chemistry, Phenotypic trait, Phenotype, Sexual dimorphism, 030104 developmental biology, Genes, Evolutionary biology, Female, International Mouse Phenotyping Consortium, Sex characteristics
Abstract: The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans., Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.
Published: 2017
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38. WD40-repeat 47 is essential for brain development via microtubule-mediated processes and autophagy

Author: Binnaz Yalcin, Meghna Kannan, Christel Wagner, Marna Roos, Bruno Rinaldi, Perrine Kretz, Lara Mcgillewie, Séverine Bär, Shilpi Minocha, Chrystelle Po, Jamel Chelly, Jean-Louis Mandel, Renato Borgatti, Amélie Piton, Stephan Collins, Craig Kinnear, Yann Herault, Sylvie Friant, Ben Loos, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), IRCCS Eugenio Medea, IRCCS, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Friant, Sylvie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Stellenbosch University, Université de Strasbourg (UNISTRA), Medical Research Council, Fédération de Médecine Translationelle de Strasbourg (FMTS), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Lausanne = University of Lausanne (UNIL), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: Erreur dates et n° de conférence dans l'url https://hal.archives-ouvertes.fr/hal-02378786.; International audience
Published: 2017

39. Integrated transcriptional analysis unveils the dynamics of cellular differentiation in the developing mouse hippocampus

Author: Giovanni Iacono, Nael Nadif Kasri, Yann Herault, Hans van Bokhoven, Aline Dubos, Hendrik G. Stunnenberg, Marco Benevento, univOAK, Archive ouverte, Radboud University [Nijmegen], Radboudumc Alzheimer Center, Radboud University Medical Center [Nijmegen], Donders Institute for Brain, Cognition and Behaviour, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and French National Infrastructure for Mouse Phenogenomics (PHENOMIN)
Subjects: 0301 basic medicine, Cell type, Cellular differentiation, Cell, lcsh:Medicine, Hippocampus, Computational biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, Single-cell analysis, medicine, Animals, lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Molecular Biology, Neurons, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinary, Gene Expression Profiling, lcsh:R, RNA, High-Throughput Nucleotide Sequencing, Cell Differentiation, Gene expression profiling, 030104 developmental biology, medicine.anatomical_structure, lcsh:Q, Single-Cell Analysis, 030217 neurology & neurosurgery
Abstract: The ability to assign expression patterns to the individual cell types that constitute a tissue is a major challenge. This especially applies to brain, given its plethora of different, functionally interconnected cell types. Here, we derived cell type-specific transcriptome signatures from existing single cell RNA data and integrated these signatures with a newly generated dataset of expression (bulk RNA-Seq) of the postnatal developing mouse hippocampus. This integrated analysis allowed us to provide a comprehensive and unbiased prediction of the differentiation drivers for 11 different hippocampal cell types and describe how the different cell types interact to support crucial developmental stages. Our results provide a reliable resource of predicted differentiation drivers and insights into the multifaceted aspects of the cells in hippocampus during development.
Published: 2017
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40. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Author: Marie-Christine Birling, Chantal Sellier, Frank Ruffenach, Cécile Martinat, Marie Wattenhofer-Donzé, Stéphane Viville, Ronald A.M. Buijsen, Mustapha Oulad-Abdelghani, Hamid Meziane, Peter K. Todd, Alexandre Vincent, Guillaume Pavlovic, Pascal Eberling, Hugues Jacobs, Verónica Martínez-Cerdeño, Flora Tassone, Marie-France Champy, Laura Jung, Fang He, Nicolas Charlet-Berguerand, Philippe Tropel, Mathieu Anheim, Angeline Gaucherot, Tania Sorg, Renate K. Hukema, Mathilde Joint, Rob Willemsen, Sam Natla, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Michigan [Ann Arbor], University of Michigan System, Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Hôpital de Hautepierre [Strasbourg], University of California [Davis] (UC Davis), University of California, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Nouvel Hôpital Civil de Strasbourg, Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), Université d'Évry-Val-d'Essonne (UEVE), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Association française contre les myopathies (AFM-Téléthon), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), CHU Strasbourg, University of California (UC), Dieterle, Stéphane, and Clinical Genetics
Subjects: Male, 0301 basic medicine, Untranslated region, MESH: Ataxia, [SDV]Life Sciences [q-bio], MESH: Tremor, MESH: Nuclear Lamina, Pathogenesis, Fragile X Mental Retardation Protein, Mice, [SCCO]Cognitive science, Tremor, MESH: Trinucleotide Repeat Expansion, MESH: Animals, Induced pluripotent stem cell, ComputingMilieux_MISCELLANEOUS, Genetics, Fragile X Tremor/Ataxia Syndrome, MESH: Peptides, MESH: Real-Time Polymerase Chain Reaction, General Neuroscience, neurodegeneration, Brain, Translation (biology), 3. Good health, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], MESH: Protein Biosynthesis, Nuclear lamina, MESH: Membrane Proteins, MESH: Fragile X Syndrome, medicine.symptom, congenital, hereditary, and neonatal diseases and abnormalities, near-cognate codon, Ataxia, MESH: Mice, Transgenic, Neuroscience(all), Mice, Transgenic, Biology, Real-Time Polymerase Chain Reaction, MESH: Fragile X Mental Retardation Protein, Article, MESH: Brain, 03 medical and health sciences, RAN translation, medicine, Animals, Humans, RNA, Messenger, MESH: Mice, MESH: RNA, Messenger, Nuclear Lamina, MESH: Humans, Membrane Proteins, RNA, [SCCO] Cognitive science, microsatellite expansion, MESH: Male, nervous system diseases, 030104 developmental biology, Fragile X Syndrome, Protein Biosynthesis, Peptides, Trinucleotide Repeat Expansion, MESH: DNA-Binding Proteins
Abstract: Summary Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS., Highlights • CGG repeats in the 5′ UTR of FMR1 are translated through initiation to an ACG codon • Translation of CGG repeats in the polyglycine protein, FMRpolyG, is toxic in mice • FMRpolyG binds and disrupts protein of the nuclear lamina, Sellier et al. show that translation of expanded CGG repeats located in the 5′ UTR of the FMR1 gene require an upstream ACG near-cognate initiation codon. Translation of CGG repeats into a short polyglycine-containing protein, FMRpolyG, is pathogenic in mouse models.
Published: 2017
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41. Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies

Author: Loic Lindner, Patrick T. Reilly, Marie-France Champy, Aline Dubos, Hervé Luche, Yann Herault, Isabelle Goncalves Da Cruz, Solène Jaubert, Hugues Jacobs, Tania Sorg, Marie Malissen, Manuel Mark, Thomas W. Rosahl, John S. Mudgett, Guillaume Pavlovic, Roy Combe, Olivia Wendling, French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA), Merck Research Laboratories, and univOAK, Archive ouverte
Subjects: 0301 basic medicine, medicine.medical_specialty, Multiple Organ Failure, lcsh:Medicine, Receptors, Cell Surface, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Gene product, 03 medical and health sciences, Gene Knockout Techniques, Mice, Internal medicine, Renin–angiotensin system, medicine, Animals, lcsh:Science, Receptor, ATP6AP2, Kidney, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, lcsh:R, Phenotype, Survival Analysis, Cell biology, Proton-Translocating ATPases, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Targeted drug delivery, lcsh:Q, Haploinsufficiency
Abstract: ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety.
Published: 2017
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42. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Author: David J. Adams, Jamel Chelly, Lara Mcgillewie, Christel Wagner, Ben Loos, Bruno Rinaldi, Sylvie Friant, Stephan C. Collins, Craig J. Kinnear, Perrine F. Kretz, Renato Borgatti, Yann Herault, Jean-Louis Mandel, Juliette D. Godin, Efil Bayam, Binnaz Yalcin, Chrystelle Po, Meghna Kannan, Marna Roos, Shilpi Minocha, Séverine Bär, Peggy Tilly, Claire Chevalier, Amélie Piton, Friant, Sylvie, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), IRCCS Eugenio Medea, IRCCS, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut Clinique de la Souris (ICS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), CNRS (S.F.), INSERM (E.B. and S.F.), Strasbourg University (S.F.), Initiatives d'Excellence (IDEX) 2015 Attractivite (S.B.), and Grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d'Avenir ANR-10-IDEX-0002-02 (to B.Y. and J.D.G.). C.K. is supported by funding from the South African Medical Research Council. B.Y. is supported by the Jerome Lejeune Foundation, the French National Research Agency (ANR-11-PDOC-0029), and the Gutenberg Circle., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Male, 0301 basic medicine, Microcephaly, autophagy, WD40 Repeats, Microtubule-associated protein, [SDV]Life Sciences [q-bio], Lissencephaly, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Microtubules, Mice, 03 medical and health sciences, 0302 clinical medicine, WD40 repeat, Cell Movement, medicine, Animals, microcephaly, Growth cone, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Neurons, Multidisciplinary, Corpus Callosum Agenesis, Stem Cells, WD40-repeat proteins, Microfilament Proteins, Neurogenesis, Brain, medicine.disease, Neural stem cell, Mice, Inbred C57BL, corpus callosum agenesis, [SDV] Life Sciences [q-bio], neurogenesis, Phenotype, 030104 developmental biology, PNAS Plus, Female, Microtubule-Associated Proteins, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1 , Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
Published: 2017
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43. RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents

Author: Benoit Petit-Demoulière, Elodie Schneider, Jean-Paul Humbert, Guy Simonnet, Caroline Ancel, Meric Ben Boujema, Valérie Utard, Hamid Meziane, Frédéric Simonin, Massimiliano Beltramo, Jean-Jacques Bourguignon, Frédéric Bihel, Séverine Schneider, Emilie Laboureyras, Khadija Elhabazi, Brigitte Ilien, Isabelle Bertin, Valérie Simonneaux, Raphaëlle Quillet, Martine Schmitt, Bernard Bucher, Tania Sorg, UMR 7242, Biotechnologie et Signalisation Cellulaire, Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), UMR 5287, Homéostasie-Allostasie-Pathologie-Réhabilitation, Université de Bordeaux (UB), UPR 3112, Institut des Neurosciences Cellulaires et Intégratives, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), UMR 7213, Laboratoire Biophotonique et Pharmacologie, Institut de Génétique et de Biologie Moléculaire et Cellulaire (INSERM/CNRS), INSERM/CNRS, Institut Clinique de la Souris, UMR 7104, U 964, Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS, INSERM, Université de Strasbourg, Alsace BioValley and by grants from SATT Conectus, Agence National de la Recherche (ANR 08 EBIO 014.02, ANR-13-BSV1-0001), Conseil Régional d’Alsace (Pharmadol), Communauté Urbaine de Strasbourg (Pharmadol), ICFRC (Pharmadol), OSEO (Pharmadol), Direction Générale des Entreprises (Pharmadol), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Équipe 'Rythme, vie et mort de la rétine', Université de Strasbourg (UNISTRA)-Institut des Neurosciences Cellulaires et Intégratives (INCI)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus et Maladies Associées, Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), ProdInra, Archive Ouverte, Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Receptors, Neuropeptide, Nociception, Narcotic Antagonists, [SDV]Life Sciences [q-bio], LH secretion, Aucun, Neuropeptide FF receptor, Administration, Oral, Pharmacology, Rats, Sprague-Dawley, Mice, RF-amide peptides, Kisspeptin, NPFF receptors, Morphine analgesia, Opioid-induced hyperalgesia, Piperidines, Cricetinae, Neuropeptide FF, Receptor, ComputingMilieux_MISCELLANEOUS, Chemistry, rodent, Valine, Receptor antagonist, 3. Good health, Analgesics, Opioid, Fentanyl, Hyperalgesia, medicine.symptom, Oligopeptides, récepteur, Protein Binding, Autre (Sciences du Vivant), Agonist, medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], medicine.drug_class, receiver, CHO Cells, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cricetulus, Internal medicine, medicine, Animals, Humans, neuropeptide, opioïde, Mesocricetus, rongeur, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Antagonist, Rats, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, sécrétion de lh, Peptides
Abstract: Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 muM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction.
Published: 2017
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44. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

Author: Kevin Drenner, Jérôme Sinniger, Mélanie Jambeau, Oliver Sendscheid, Anke Witting, Jelena Scekic-Zahirovic, Tatyana A. Shelkovnikova, Marie-Christine Birling, Albert C. Ludolph, Erik Storkebaum, Sina Mersmann, Caroline Rouaux, Clotilde Lagier-Tourenne, Marina Wagner, Stéphane Dieterlé, Luc Dupuis, Xiang-Dong Fu, Hajer El Oussini, Ying Sun, Hairi Li, Friedemann Kiefer, Yu Zhou, Jinsong Qiu, Sylvie Dirrig-Grosch, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft, University of California [San Diego] (UC San Diego), University of California, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Psychology [Cardiff University], Cardiff University, University of Ulm (UUlm), Ludwig Institute for Cancer Research, Dieterle, Stéphane, and University of California (UC)
Subjects: 0301 basic medicine, Cytoplasm, amyotrophic lateral sclerosis, PY‐NLS, motor neuron degeneration, [SDV]Life Sciences [q-bio], Mutant, Inbred C57BL, frontotemporal dementia, Medical and Health Sciences, Transgenic, MESH: Spinal Cord, MESH: Heart Conduction System, [SCCO]Cognitive science, Mice, 0302 clinical medicine, Gene expression, News & Views, MESH: Animals, MESH: Xenopus, Amyotrophic lateral sclerosis, Genetics, Motor Neurons, MESH: Middle Aged, MESH: RNA-Binding Protein FUS, General Neuroscience, Neurodegeneration, Brain, Biological Sciences, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Spinal Cord, MESH: HEK293 Cells, Knockout mouse, MESH: Nucleotide Motifs, MESH: Motor Neurons, MESH: Mutation, MESH: Myotonic Dystrophy, MESH: Mice, Transgenic, Mice, Transgenic, Biology, PY-NLS, General Biochemistry, Genetics and Molecular Biology, MESH: Sodium Channels, 03 medical and health sciences, MESH: Brain, MESH: Mice, Inbred C57BL, Information and Computing Sciences, medicine, Animals, Molecular Biology, Loss function, FUS, MESH: Humans, MESH: Molecular Sequence Data, General Immunology and Microbiology, MESH: Cytoplasm, MESH: NAV1.5 Voltage-Gated Sodium Channel, [SCCO] Cognitive science, Motor neuron, medicine.disease, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, MESH: RNA-Binding Proteins, Mutation, RC0321, RNA-Binding Protein FUS, MESH: Exons, MESH: Female, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.
Published: 2016
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45. The cell proliferation antigen Ki-67 organises heterochromatin

Author: Karim Mrouj, Nikolaos Parisis, Michal Sobecki, Philippe Jay, Daniel Fisher, Liliana Krasinska, Jérôme Déjardin, François Gerbe, Serge Urbach, Marcos Malumbres, Susana Prieto, Alain Camasses, Vjekoslav Dulic, Denis L. J. Lafontaine, Robert Feil, David Llères, Manuel Eguren, Emilien Nicolas, Sonia Hem, Alexandre David, Marie-Christine Birling, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Libre de Bruxelles [Bruxelles] (ULB), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Center for Indlejrede Software Systemer (CISS), Aalborg University [Denmark] (AAU), Institut Clinique de la Souris (ICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Center for Microscopy and Molecular Imaging (IBMM - CMMI), Agence Nationale de la Recherche (Francia), Ligue Nationale Contre le Cancer (Francia), Fondation pour la recherche médicale (Francia), RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Fonds de la Recherche Nationale, Université Libre de Bruxelles, Charleroi-Gosselies, Belgium, Université de Montpellier (UM), Spanish National Cancer Research Centre, Madrid, Spain, ICS, Mouse Clinical Institute, Illkirch-Graffenstaden, France, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA), Université libre de Bruxelles (ULB), Spanish National Cancer Research Center (CNIO), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PRIETO, Susana, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Université de Montpellier ( UM ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform ( MSPP ), Institut National de la Recherche Agronomique ( INRA ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), and Fisher, Daniel
Subjects: 0301 basic medicine, Mouse, Xenopus, Gene Expression, cellule mammaire, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, Heterochromatin, Immunologie, Gene expression, cell biology, Nuclear protein, Biology (General), ComputingMilieux_MISCELLANEOUS, Cell proliferation, antigen, regulator, heterochromatin, cell proliferation, cell biology, Ki-67, mouse, human, gene expression, Nucleologenesis, Vegetal Biology, biology, Ki-67, cell proliferation, heterochromatin, human, mouse, General Neuroscience, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], General Medicine, Sciences bio-médicales et agricoles, Chromatin, Cell biology, Histone, regulator, Gene Knockdown Techniques, Antigen KI-67, Medicine, Research Article, expression génique, QH301-705.5, Science, Hhuman, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, antigen, régulateur, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gene silencing, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, antigène, General Immunology and Microbiology, [ SDV ] Life Sciences [q-bio], antigène, cellule mammaire, expression génique, régulateur, Neurosciences cognitives, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 030104 developmental biology, Ki-67 Antigen, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], biology.protein, gene expression, Microbiologie et protistologie [bacteriol.virolog.mycolog.], [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Biologie végétale
Abstract: Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2016
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46. Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability

Author: Fabrice Riet, Sophie Reibel-Foisset, Noemi Morello, Maurizio Giustetto, Jamel Chelly, Mohammed Selloum, Thierry Bienvenu, Bassem Hiba, Ginevra Zanni, Eleonora Calcagno, Malik Khelfaoui, Yann Humeau, Hamid Meziane, Yann Herault, Pierre Billuart, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Interdisciplinary Institute for Neuroscience, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie et de génétique moléculaire [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dipartimento di Neuroscienza, Università degli studi di Torino (UNITO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et embryologie moléculaires (IEM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]
Subjects: 0301 basic medicine, Adult, RHOA, Dendritic spine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], autism, Synaptic Transmission, 03 medical and health sciences, Mice, synaptopathies, 0302 clinical medicine, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Intellectual disability, Neuroplasticity, Genetics, medicine, Animals, Humans, Molecular Biology, Rho-associated protein kinase, Genetics (clinical), Loss function, biology, Behavior, Animal, GTPase-Activating Proteins, Fasudil, Brain, Nuclear Proteins, autism, synaptopathies, dendritic spines, intellectual disability, General Medicine, dendritic spines, medicine.disease, 3. Good health, Cytoskeletal Proteins, Disease Models, Animal, 030104 developmental biology, Schizophrenia, intellectual disability, biology.protein, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Loss of function mutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodent models suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiological mechanisms with other cognitive disorders. Variants of this gene have been also identified in autism spectrum disorder and schizophrenia. The advanced understanding of the mechanisms underlying OPHN1-related ID, allowed us to develop a therapeutic approach targeting the Ras homolog gene family, member A (RHOA) signalling pathway and repurpose Fasudil-a well-tolerated Rho Kinase (ROCK) and Protein Kinase A (PKA) inhibitor-as a treatment of ID. We have previously shown ex-vivo its beneficial effect on synaptic transmission and plasticity in a mouse model of the OPHN1 loss of function. Here, we report that chronic treatment in adult mouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognition memory and limits the brain ventricular dilatation observed in Ophn1 À/y. However, deficits in working and spatial memories are partially or not rescued by the treatment. These results highlight the potential of Fasudil treatment in synaptopathies and also the need for multiple therapeutic approaches especially in adult where brain plasticity is reduced. †
Published: 2016
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47. Introduction to Mammalian Genome Special Issue: Genome Editing

Author: Lydia Teboul, Yann Herault, Bruce Whitelaw, Cynthia L. Smith, univOAK, Archive ouverte, MRC Harwell Institute [UK], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), The Jackson Laboratory [Bar Harbor] (JAX), and University of Edinburgh
Subjects: Gene Editing, Mammals, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genome, [SDV.GEN] Life Sciences [q-bio]/Genetics, Computational biology, Biology, Human genetics, Genome editing, Animals, Mammalian genome, Introductory Journal Article
Abstract: No abstract available
Published: 2017
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48. Parp2 is required for the differentiation of post-meiotic germ cells: Identification of a spermatid-specific complex containing Parp1, Parp2, TP2 and HSPA2

Author: A. van Dorsselear, Valérie Schreiber, Manuel Mark, Saadi Khochbin, Françoise Dantzer, Delphine Quénet, Jérôme Govin, Peney, Maité, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Male, Spermiogenesis, Poly ADP ribose polymerase, Molecular Sequence Data, Poly (ADP-Ribose) Polymerase-1, Mice, 03 medical and health sciences, Prophase, Chlorocebus aethiops, medicine, Animals, Humans, HSP70 Heat-Shock Proteins, Amino Acid Sequence, 030304 developmental biology, Mice, Knockout, 0303 health sciences, biology, Spermatid, 030302 biochemistry & molecular biology, Nuclear Proteins, Sciences du Vivant [q-bio]/Biotechnologies, Cell Differentiation, Cell Biology, Spermatids, Cell biology, Chromatin, DNA-Binding Proteins, Mice, Inbred C57BL, Meiosis, Histone, medicine.anatomical_structure, Chaperone (protein), COS Cells, biology.protein, Poly(ADP-ribose) Polymerases, Germ cell
Abstract: International audience; Spermiogenesis is a complex male germ cell post-meiotic differentiation process characterized by dramatic changes in chromatin structure and function, including chromatin condensation, transcriptional inhibition and the sequential replacement of histones by transition proteins and protamines. Recent advances, in mammalian cells, suggest a possible role of poly(ADP-ribosyl)ation catalyzed by Parp1 and/or Parp2 in this process. We have recently reported severely compromised spermiogenesis in Parp2-deficient mice characterized by a marked delay in nuclear elongation whose molecular mechanisms remain however unknown. Here, using in vitro protein-protein interaction assays, we show that Parp2 interacts significantly with both the transition protein TP2 and the transition chaperone HSPA2, whereas Parp1 binds weakly to HSPA2. Parp2-TP2 interaction is partly mediated by poly(ADP-ribosyl)ation. Only Parp1 poly(ADP-ribosyl)ates HSPA2. In addition, a detailed analysis of spermatid maturation in Parp2-deficient mice, combining immunohistochemistry and electron microscopic approaches, reveals a loss of spermatids expressing TP2, a defect in chromatin condensation and abnormal formation of the manchette microtubules that, together, contribute to spermatid-specific cell death. In conclusion, we propose both Parps as new participants of a spermatid-specific protein complex involved in genome reorganization throughout spermiogenesis.
Published: 2009
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49. mTOR complex 2 in adipose tissue negatively controls whole-body growth

Author: Johan Auwerx, Michael N. Hall, Nadine Cybulski, Pazit Polak, Markus A. Rüegg, Biozentrum [Basel, Suisse], University of Basel (Unibas), Institut Clinique de la Souris (ICS), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Peney, Maité
Subjects: Male, medicine.medical_treatment, MESH: Insulin-Like Growth Factor I, Adipose tissue, Growth, mTORC1, MESH: Base Sequence, Polymerase Chain Reaction, MESH: Mice, Knockout, mTORC2, Mice, Absorptiometry, Photon, MESH: Cholesterol, 0302 clinical medicine, MESH: Animals, Insulin-Like Growth Factor I, MESH: Fatty Liver, Mice, Knockout, 0303 health sciences, Multidisciplinary, TOR Serine-Threonine Kinases, Biological Sciences, MESH: Adiponectin, Cholesterol, Adipose Tissue, Adiponectin, MESH: Adipose Tissue, MESH: DNA Primers, medicine.medical_specialty, Normal diet, MESH: Carrier Proteins, MESH: Absorptiometry, Photon, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Mice, MESH: Protein Kinases, Protein kinase B, PI3K/AKT/mTOR pathway, DNA Primers, 030304 developmental biology, MESH: Growth, Base Sequence, Growth factor, RPTOR, MESH: Polymerase Chain Reaction, MESH: Male, Fatty Liver, Rapamycin-Insensitive Companion of mTOR Protein, Endocrinology, Carrier Proteins, Protein Kinases, 030217 neurology & neurosurgery
Abstract: Mammalian target of rapamycin (mTOR), a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors, is found in 2 structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. mTORC2, which consists of rictor, mSIN1, mLST8, and mTOR, is activated by insulin/IGF1 and phosphorylates Ser-473 in the hydrophobic motif of Akt/PKB. Though the role of mTOR in single cells is relatively well characterized, the role of mTOR signaling in specific tissues and how this may contribute to overall body growth is poorly understood. To examine the role of mTORC2 in an individual tissue, we generated adipose-specific rictor knockout mice ( rictor ad−/− ). Rictor ad−/− mice are increased in body size due to an increase in size of nonadipose organs, including heart, kidney, spleen, and bone. Furthermore, rictor ad−/− mice have a disproportionately enlarged pancreas and are hyperinsulinemic, but glucose tolerant, and display elevated levels of insulin-like growth factor 1 (IGF1) and IGF1 binding protein 3 (IGFBP3). These effects are observed in mice on either a high-fat or a normal diet, but are generally more pronounced in mice on a high-fat diet. Our findings suggest that adipose tissue, in particular mTORC2 in adipose tissue, plays an unexpectedly central role in controlling whole-body growth.
Published: 2009
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50. The Pro12Ala PPARγ2 Variant Determines Metabolism at the Gene-Environment Interface

Author: Marie-France Champy, Carmen Argmann, Johan Auwerx, Nassim Dali-Youcef, Hana Koutnikova, Sami Heikkinen, Markku Laakso, Eric E. Schadt, Jerome N. Feige, Peney, Maité, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.I.Virtanen Institute for Molecular Sciences, University of Kuopio, Institut Clinique de la Souris (ICS), Laboratoire de Biochimie Générale et Spécialisée, Hôpitaux Universitaires de Strasbourg, Rosetta Inpharmatics LLC, Merck & Co. Inc, Department of Medicine, Ecole Polytechnique Fédérale de Lausanne (EPFL), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), and DALI-YOUCEF, Nassim
Subjects: Gene isoform, medicine.medical_specialty, Physiology, [SDV]Life Sciences [q-bio], Adipose Tissue, White, Longevity, HUMDISEASE, 030209 endocrinology & metabolism, Context (language use), Biology, Carbohydrate metabolism, medicine.disease_cause, Body Mass Index, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, medicine, Animals, Insulin, Protein Isoforms, Genetic Predisposition to Disease, Gene Knock-In Techniques, Receptor, Molecular Biology, Alleles, 030304 developmental biology, 2. Zero hunger, Regulation of gene expression, 0303 health sciences, Mutation, Adiponectin, Cell Biology, [SDV.ETH] Life Sciences [q-bio]/Ethics, Lipids, Diet, [SDV.ETH]Life Sciences [q-bio]/Ethics, [SDV] Life Sciences [q-bio], PPAR gamma, Endocrinology, Glucose, Amino Acid Substitution, Gene Expression Regulation, Metabolic control analysis
Abstract: International audience; The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARgamma2) variant Pro12Ala in human populations has been widely debated. We demonstrate, using a Pro12Ala knockin model, that on chow diet, Ala/Ala mice are leaner, have improved insulin sensitivity and plasma lipid profiles, and have longer lifespans. Gene-environment interactions played a key role as high-fat feeding eliminated the beneficial effects of the Pro12Ala variant on adiposity, plasma lipids, and insulin sensitivity. The underlying molecular mechanisms involve changes in cofactor interaction and adiponectin signaling. Altogether, our results establish the Pro12Ala variant of Ppargamma2 as an important modulator in metabolic control that strongly depends on the metabolic context.
Published: 2009
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