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1. CEP250 is Required for Maintaining Centrosome Cohesion in the Germline and Fertility in Male Mice

Author

Sandrine Floriot, Laura Bellutti, Johan Castille, Pauline Moison, Sébastien Messiaen, Bruno Passet, Laurent Boulanger, Abdelhak Boukadiri, Sophie Tourpin, Christian Beauvallet, Marthe Vilotte, Julie Riviere, Christine Péchoux, Maud Bertaud, Jean-Luc Vilotte, and Gabriel Livera

Subjects
centrosome, spermatogenesis, meiosis, DNA damage, oogenesis, Biology (General), QH301-705.5
Abstract

Male gametogenesis involves both mitotic divisions to amplify germ cell progenitors that gradually differentiate and meiotic divisions. Centrosomal regulation is essential for both types of divisions, with centrioles remaining tightly paired during the interphase. Here, we generated and characterized the phenotype of mutant mice devoid of Cep250/C-Nap1, a gene encoding for a docking protein for fibers linking centrioles, and characterized their phenotype. The Cep250-/- mice presented with no major defects, apart from male infertility due to a reduction in the spermatogonial pool and the meiotic blockade. Spermatogonial stem cells expressing Zbtb16 were not affected, whereas the differentiating spermatogonia were vastly lost. These cells displayed abnormal γH2AX-staining, accompanied by an increase in the apoptotic rate. The few germ cells that survived at this stage, entered the meiotic prophase I and were arrested at a pachytene-like stage, likely due to synapsis defects and the unrepaired DNA double-strand breaks. In these cells, centrosomes split up precociously, with γ-tubulin foci being separated whereas these were closely associated in wild-type cells. Interestingly, this lack of cohesion was also observed in wild-type female meiocytes, likely explaining the normal fertility of Cep250-/- female mice. Taken together, this study proposes a specific requirement of centrosome cohesion in the male germline, with a crucial role of CEP250 in both differentiating spermatogonia and meiotic spermatocytes.

Published
2022
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4. Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health.

Author

Amandine Duchesne, Anne Vaiman, Johan Castille, Christian Beauvallet, Pauline Gaignard, Sandrine Floriot, Sabrina Rodriguez, Marthe Vilotte, Laurent Boulanger, Bruno Passet, Olivier Albaric, François Guillaume, Abdelhak Boukadiri, Laurence Richard, Maud Bertaud, Edouard Timsit, Raphaël Guatteo, Florence Jaffrézic, Pierre Calvel, Louise Helary, Rachid Mahla, Diane Esquerré, Christine Péchoux, Sophie Liuu, Jean-Michel Vallat, Didier Boichard, Abdelhamid Slama, and Jean-Luc Vilotte

Subjects
Genetics, QH426-470
Abstract

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the "Turning calves syndrome", a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics.

Published
2017
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5. Analysis of Polycerate Mutants Reveals the Evolutionary Co-option of HOXD1 for Horn Patterning in Bovidae

Author

Daniele Bigi, Fiona Menzi, Slim Ben Jemaa, Marie-Christine Deloche, Aurélien Capitan, Johannes A. Lenstra, Marina Naval-Sanchez, Ivica Medugorac, Nathalie Hirter, Gwenola Tosser-Klopp, Diane Esquerre, Coralie M. Reich, Julia M. Paris, Rose-Marie Arbogast, Amandine Blin, Abdelhak Boukadiri, Aurélie Hintermann, Julie Rivière, Denis Duboule, Raphaël Cornette, Cécile Donnadieu, Marie-Dominique Wandhammer, Gjoko Bunevski, Louisa Gidney, Michael Stache, Isabelle Palhiere, Renate Schafberg, James Kijas, Claude Guintard, Joséphine Lesur, Jozsef Zakany, Rachel Rupp, Noelle E. Cockett, John Hedges, Ashleigh Haruda, Philippe Bardou, Olivier Putelat, Tracy Hadfield, Alain Pinton, Ockert Greyvenstein, Aurélie Allais-Bonnet, Este Van Marle-Koster, Eric Pailhoux, Coralie Danchin-Burge, David G. Riley, Cécile Grohs, Benjamin J. Hayes, Cord Drögemüller, Allice, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Martin-Luther-University Halle-Wittenberg, Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Geneva [Switzerland], University of Bologna, Ludwig Maximilian University [Munich] (LMU), Archéologie d'Alsace, Archéologie et histoire ancienne : Méditerranée - Europe (ARCHIMEDE), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Texas A&M University [College Station], Utah State University (USU), Université de Carthage - University of Carthage, Ss. Cyril and Methodius University in Skopje, University of Bern, Manx Text, Manx Loaghtan Sheep Breeders (MLSBG), Utrecht University [Utrecht], Rent a Peasant, Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Musée Zoologique de Strasbourg, Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Acquisition et Analyse de Données pour l'Histoire naturelle (2AD), 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), Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de l'élevage (IDELE), Agriculture Victoria (AgriBio), Tshwane University of Technology [Pretoria] (TUT), Queensland Alliance for Agriculture and Food Innovation (QAAFI), University of Queensland [Brisbane], CSIRO Agriculture and Food (CSIRO), Ecole Polytechnique Fédérale de Lausanne (EPFL), Collège de France (CdF (institution)), Allais-Bonnet, Aurélie, Hintermann, Aurélie, Deloche, Marie-Christine, Cornette, Raphaël, Bardou, Philippe, Naval-Sanchez, Marina, Pinton, Alain, Haruda, Ashleigh, Grohs, Cécile, Zakany, Jozsef, Bigi, Daniele, Medugorac, Ivica, Putelat, Olivier, Greyvenstein, Ockert, Hadfield, Tracy, Jemaa, Slim Ben, Bunevski, Gjoko, Menzi, Fiona, Hirter, Nathalie, Paris, Julia M, Hedges, John, Palhiere, Isabelle, Rupp, Rachel, Lenstra, Johannes A, Gidney, Louisa, Lesur, Joséphine, Schafberg, Renate, Stache, Michael, Wandhammer, Marie-Dominique, Arbogast, Rose-Marie, Guintard, Claude, Blin, Amandine, Boukadiri, Abdelhak, Rivière, Julie, Esquerré, Diane, Donnadieu, Cécile, Danchin-Burge, Coralie, Reich, Coralie M, Riley, David G, Marle-Koster, Este van, Cockett, Noelle, Hayes, Benjamin J, Drögemüller, Cord, Kijas, Jame, Pailhoux, Eric, Tosser-Klopp, Gwenola, Duboule, Deni, Capitan, Aurélien, École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT], Université de Genève = University of Geneva (UNIGE), University of Bologna/Università di Bologna, Ss. Cyril and Methodius University in Skopje (UKIM), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Collège de France - Chaire internationale Évolution des génomes et développement

Subjects
0106 biological sciences, Male, co-option, translocation, AcademicSubjects/SCI01180, regulatory mutation, 01 natural sciences, Hox genes, Hox gene, genes, 610 Medicine & health, Bilateria, time, Horns, 0303 health sciences, biology, Ecology, 630 Agriculture, Goats, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Gene Expression Regulation, Developmental, alignment, Morphogenetic field, Biological Evolution, [SDV.BDD.MOR] Life Sciences [q-bio]/Development Biology/Morphogenesis, 590 Animals (Zoology), Haploinsufficiency, transcription, Biometry, Evolution, growth, Locus (genetics), Mice, Transgenic, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, 010603 evolutionary biology, 03 medical and health sciences, goat and sheep genomics, Behavior and Systematics, framework, Genetics, Animals, Allele, Gene, Molecular Biology, Discoveries, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Homeodomain Proteins, locus, Sheep, Horn (anatomy), AcademicSubjects/SCI01130, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, sequence, biology.organism_classification, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Evolutionary biology, Mutation, genome-wide association, 570 Life sciences, goat and sheep genomic
Abstract

In the course of evolution, pecorans (i.e., higher ruminants) developed a remarkable diversity of osseous cranial appendages, collectively referred to as “headgear,” which likely share the same origin and genetic basis. However, the nature and function of the genetic determinants underlying their number and position remain elusive. Jacob and other rare populations of sheep and goats are characterized by polyceraty, the presence of more than two horns. Here, we characterize distinct POLYCERATE alleles in each species, both associated with defective HOXD1 function. We show that haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae.

Published
2021

6. Rapid discovery of de novo deleterious mutations in cattle enhances the value of livestock as model species

Author

Bourneuf, E., Otz, P., Pausch, H., Jagannathan, V., Michot, P., Grohs, C., Piton, G., Ammermüller, S., Deloche, M.-C., Fritz, S., Leclerc, H., Péchoux, C., Boukadiri, A., Hozé, C., Saintilan, R., Créchet, F., Mosca, M., Segelke, D., Guillaume, F., Bouet, S., Baur, A., Vasilescu, A., Genestout, L., Thomas, A., Allais-Bonnet, A., Rocha, D., Colle, M.-A., Klopp, C., Esquerré, D., Wurmser, C., Flisikowski, K., Schwarzenbacher, H., Burgstaller, J., Brügmann, M., Dietschi, E., Rudolph, N., Freick, M., Barbey, S., Fayolle, G., Danchin-Burge, C., Schibler, L., Bed’Hom, B., Hayes, B. J., Daetwyler, H. D., Fries, R., Boichard, D., Pin, D., Drögemüller, C., Capitan, A., Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris-Saclay, Laboratoire de Radiobiologie et d'Etude de Génome (LREG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Ecole Nationale Vétérinaire de Lyon (ENVL), Chair of Animal Breeding, Technische Universität München [München] (TUM), Institute of Genetics - Vetsuisse Faculty, Universität Bern [Bern], Allice, Laboratoire de Radiobiologie et d'Etude de Génome, Institut de l'Elevage, Plateforme de Microscopie MIMA2 MET, Institut National de la Recherche Agronomique (INRA), Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Vereinigte Informationssysteme Tierhaltung (VIT), Laboratoire d'Analyses Génétiques pour les Espèces Animales (LABOGENA), Imaging Department, University Hospital Santa Maria, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Nantes-Atlantic National College of Veterinary Medicine, Food science and Engineering, PRES Université Nantes Angers Le Mans (UNAM), Ecole Nationale Vétérinaire Agroalimentaire et de l'Alimentation Nantes Atlantique (ONIRIS), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRA), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Chair of Animal Biotechnology, Technical University of Munich (TUM), ZuchtData EDV-Dienstleistungen GmbH, Clinic for Ruminants, Ludwig-Maximilians-Universität München (LMU), Department of Pathology, Lower Saxony State Office for Consumer Protection and Food Safety, Landesuntersuchungsanstalt für das Gesundheits- und Veterinärwesen Sachsen, Veterinary Practice Zettlitz, Domaine expérimental animal du Pin (SEA), Union Montbéliarde de Testage (UMOTEST), Centre for AgriBioscience, Biosciences Research, AgriBio, Queensland Alliance for Agriculture and Food Innovation - Centre for Animal Science, University of Queensland [Brisbane], Centre for AgriBioscience - Biosciences Research, School of Applied Systems Biology, La Trobe University [Melbourne], ANR-Apisgene Bovano, AgroParisTech-Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institut de l'élevage (IDELE), Laboratoire d'Analyse Génétique pour les Espèces Animales (LABOGENA), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Universität Bern [Bern] (UNIBE), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-École nationale supérieure agronomique de Toulouse (ENSAT), Université de Toulouse (UT)-Université de Toulouse (UT), and Domaine Expérimental du Pin (DEP)

Subjects
Livestock, bovin, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, lcsh:Medicine, 610 Medicine & health, Genome-wide association studies, Article, Animals, Humans, Genetic Predisposition to Disease, Clinical genetics, lcsh:Science, Genetic Association Studies, Neural tube defects, Animal breeding, séquence du génome complet, modèle pour l'homme, 630 Agriculture, Whole Genome Sequencing, lcsh:R, Genetic Diseases, Inborn, Genomics, Pedigree, Disease Models, Animal, Phenotype, Next-generation sequencing, Mutation, 570 Life sciences, biology, 590 Animals (Zoology), lcsh:Q, Cattle, anomalie génétique
Abstract

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans., Scientific Reports, 7 (1), ISSN:2045-2322

Published
2017

7. A short double-stapled peptide inhibits respiratory syncytial virus entry and spreading

Author

Geneviève Mottet-Osman, Origène Nyanguile, Elodie Baechler, Miriam Arrell, Abdelhak Boukadiri, Ronan Le Goffic, Marie Galloux, Julien Héritier, Thibaut Larcher, Marie-Anne Rameix-Welti, Jean-Manuel Segura, Vanessa Gaillard, Dominique Garcin, Jean-François Eléouët, Haute École Spécialisée de Suisse occidentale Valais (HES-SO Valais-Wallis), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Department of Microbiology and Molecular Medicine, University of Geneva [Switzerland], Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Laboratoire de Microbiologie, Hôpital Raymond Poincareé, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Commission for Technology and Innovation CTI [12.868.1], Swiss Confederation, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, and UFR des Sciences de la Santé Simone Veil

Subjects
0301 basic medicine, Protein Conformation, alpha-Helical, viruses, respiratory syncytial virus, [SDV]Life Sciences [q-bio], Peptide, Plasma protein binding, Respiratory syncytial virus, stapled peptides, Virus Replication, respiratory syncytial viruses, Mice, Pharmacology (medical), Peptide sequence, chemistry.chemical_classification, ddc:616, Mice, Inbred BALB C, Protein Stability, virus respiratoire syncytial, 3. Good health, Amino acid, Stapled peptides, Infectious Diseases, Female, Protein Binding, Respiratory Syncytial Virus Infections, Biology, Antiviral Agents, Virus, 03 medical and health sciences, Viral entry, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Administration, Intranasal, Pharmacology, Binding Sites, Sequence Homology, Amino Acid, Virus Internalization, Virology, Heptad repeat, 030104 developmental biology, chemistry, Viral replication, Amino Acid Substitution, Respiratory Syncytial Virus, Human, Proteolysis, Peptides, Sequence Alignment, Viral Fusion Proteins, HeLa Cells
Abstract

Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled-peptide scan across the HR2 domain of the respiratory syncytial virus (RSV) F protein with the aim to identify a minimal domain capable of disrupting the formation of the postfusion six-helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides that display nanomolar potency in HEp-2 cells and are exceptionally robust to proteolytic degradation. By replacing each amino acid of the peptides by an alanine, we found that the substitution of residues 506 to 509, located in a patch of polar contacts between HR2 and HR1, severely affected inhibition. Finally, we show that intranasal delivery of the most potent peptide to BALB/c mice significantly decreased RSV infection in upper and lower respiratory tracts. The discovery of this minimal HR2 sequence as a means for inhibition of RSV infection provides the basis for further medicinal chemistry efforts toward developing RSV fusion antivirals.

Published
2017

8. Bacteria isolated from lung modulate asthma susceptibility in mice

Author

Remot, Aude, Descamps, Delphyne, Noordine, Marie-Louise, Boukadiri, Abdelhak, Mathieu, Elliot, Robert, Véronique, Riffault, Sabine, Lambrecht, Bart, Langella, Philippe, Hammad, Hamida, Thomas, Muriel, Infectiologie Animale et Santé Publique - IASP (Nouzilly, France), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Unité de recherche Virologie et Immunologie Moléculaires (VIM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Génétique Animale et Biologie Intégrative (GABI), VIB Inflammation Research Center, Department of Respiratory Medicine, Imperial College London, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), and AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
COLONIC EPITHELIUM, mice, [SDV]Life Sciences [q-bio], AIRWAY MICROBIOME, souris, Bacterial Physiological Phenomena, DENDRITIC CELLS, COLONIZATION, lung, EARLY-LIFE, ALLERGIC DISEASES, INFLAMMATION, microbiote, Medicine and Health Sciences, Animals, Bacteria, GUT MICROBIOTA, Biology and Life Sciences, Dust, Allergens, Asthma, respiratory tract diseases, asthme, Mice, Inbred C57BL, poumon, Original Article, IMMUNE-SYSTEM, Disease Susceptibility, bronchial asthma, RESPONSES
Abstract

International audience; Asthma is a chronic, non-curable, multifactorial disease with increasing incidence in industrialcountries. This study evaluates the direct contribution of lung microbial components in allergicasthma in mice. Germ-Free and Specific-Pathogen-Free mice display similar susceptibilities to HouseDust Mice-induced allergic asthma, indicating that the absence of bacteria confers no protection orincreased risk to aeroallergens. In early life, allergic asthma changes the pattern of lung microbiota,and lung bacteria reciprocally modulate aeroallergen responsiveness. Primo-colonizing cultivablestrains were screened for their immunoregulatory properties following their isolation from neonatallungs. Intranasal inoculation of lung bacteria influenced the outcome of allergic asthma development:the strain CNCM I 4970 exacerbated some asthma features whereas the pro-Th1 strain CNCM I 4969had protective effects. Thus, we confirm that appropriate bacterial lung stimuli during early life arecritical for susceptibility to allergic asthma in young adults

Published
2017

9. Structurally related odorant ligands of the olfactory receptor OR51E2 differentially promote metastasis emergence and tumor growth

Author

Sanz, Guenhaël, Leray, Isabelle, Grebert, Denise, Antoine, Sharmilee, Acquistapace, Adrien, Muscat, Adeline, Boukadiri, Abdelhak, Mir, Lluis M., Neurobiologie de l'olfaction (NBO), Institut National de la Recherche Agronomique (INRA), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, NBO, Neurobiologie de l'Olfaction et de la Prise Alimentaire (NOPA), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, INRA, CNRS, Fondation EDF, AgroParisTech-Institut National de la Recherche Agronomique (INRA), and Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, [SDV]Life Sciences [q-bio], olfactory receptors, Prostatic Neoplasms, tumor progression, odorant ligands, Receptors, Odorant, prostate cancer, Neoplasm Proteins, Up-Regulation, Mice, Cell Movement, Cell Line, Tumor, Disease Progression, Animals, Humans, Neoplasm Metastasis, Norisoprenoids, Neoplasm Transplantation, Research Paper
Abstract

Olfactory receptors are G protein-coupled receptors. Some of them are expressed in tumor cells, such as the OR51E2 receptor overexpressed in LNCaP prostate cancer cells. It is considered a prostate tumor marker. We previously demonstrated that this receptor is able to promote LNCaP cell invasiveness in vitro upon stimulation with its odorant agonist beta-ionone, leading to increased generation of metastases in vivo. In the present study, we show that even a relatively short exposure to beta-ionone is sufficient to promote metastasis emergence. Moreover, alpha-ionone, considered an OR51E2 antagonist, in fact promotes prostate tumor growth in vivo. The combination of alpha-ionone with beta-ionone triggers a higher increase in the total tumor burden than each molecule alone. To support the in vivo results, we demonstrate in vitro that alpha-ionone is a real agonist of OR51E2, mainly sustaining LNCaP cell growth, while beta-ionone mainly promotes cell invasiveness. So, while structurally close, alpha-ionone and beta-ionone appear to induce different cellular effects, both leading to increased tumor aggressiveness. This behaviour could be explained by a different coupling to downstream effectors, as it has been reported for the so-called biased ligands of other G protein-coupled receptors.

Published
2017

10. Rapid discovery of de novo deleterious mutations in cattle enhances the value of livestock as model species

Author

Pausch, H., Jagannathan, V., Michot, Pauline, Grohs, Cécile, Piton, Guillaume, Ammermüller, S, Deloche, Marie Christine, Fritz, Sebastien, Leclerc, Hélène, Péchoux, Christine, Boukadiri, Abdelhak, Hozé, Chris, Saintilan, Romain, Créchet, Françoise, Mosca, M., Segelke, D., Guillaume, François, Bouet, Stephan, Baur, Aurélia, Vasilescu, A., Genestout, L., Thomas, A., Allais Bonnet, Aurélie, Rocha, Dominique, Colle, Marie-Anne, Klopp, Christophe, Esquerre, Diane, Wurmser, C., Flisikowski, K., Schwarzenbacher, H., Burgstaller, J., Brügmann, M., Dietschi, E., Rudolph, N., Freick, M., Barbey, Sarah, Fayolle, G., Danchin-Burge, C., Schibler, L., Bed'Hom, Bertrand, Hayes, B. J., Daetwyler, H. D., Fries, R, Boichard, Didier, Pin, D., Drögemüller, C., Bourneuf, Emmanuelle, Otz, P., and Capitan, Aurélien

Subjects
bovin, anomalie génétique, séquence du génome complet, modèle pour l'homme
Abstract

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans.

Published
2017

11. Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health

Author

Duchesne, Amandine, Vaiman, Anne, Castille, Johan, Beauvallet, Christian, Gaignard, Pauline, Floriot, Sandrine, Rodriguez, Sabrina, Vilotte, Marthe, Boulanger, Laurent, Passet, Bruno, Albaric, Olivier, Guillaume, François, Boukadiri, Abdelhak, Richard, Laurence, Bertaud, Maud, Timsit, Edouard, Guatteo, Raphaël, Jaffrézic, Florence, Calvel, Pierre, Helary, Louise, Mahla, Rachid, Esquerré, Diane, Péchoux, Christine, Liuu, Sophie, Vallat, Jean-Michel, Boichard, Didier, Slama, Abdelhamid, Vilotte, Jean-Luc, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Toulouse White Biotechnology (TWB), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Centre de référence national neuropathies périphériques rares [CHU Limoges], CHU Limoges, University of Calgary, Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Institut National de la Recherche Agronomique (INRA), Laboratoire d'Analyse Génétique pour les Espèces Animales (LABOGENA), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), ANR APIS-GENE Bovano ANR-14-CE19-0011, Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-École nationale supérieure agronomique de Toulouse (ENSAT), Université de Toulouse (UT)-Université de Toulouse (UT), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT]

Subjects
Proteomics, bovin, Protein Extraction, [SDV]Life Sciences [q-bio], Artificial Gene Amplification and Extension, souris, Biochemistry, Polymerase Chain Reaction, Mitochondrial Dynamics, Phosphate Transport Proteins, Energy-Producing Organelles, Protein Metabolism, Mammals, Extraction Techniques, Animal Models, Ruminants, Mitochondrial DNA, Mitochondria, Nucleic acids, Phenotype, Experimental Organism Systems, Vertebrates, Cellular Structures and Organelles, anomalie veau tourneur, gène SLC25A46, Research Article, mice, lcsh:QH426-470, Forms of DNA, Mouse Models, Bioenergetics, Research and Analysis Methods, Mitochondrial Proteins, Polyneuropathies, Model Organisms, Bovines, Genetics, Animals, Humans, Molecular Biology Techniques, Molecular Biology, Organisms, Biology and Life Sciences, Cell Biology, DNA, lcsh:Genetics, Metabolism, Amino Acid Substitution, Amniotes, Mutation, Cattle, Mitochondrial Membrane, anomalie génétique
Abstract

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the “Turning calves syndrome”, a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics., Author summary Mitochondria are essential organelles, the site of numerous biochemical reactions, with a critical role in delivering energy to cells, particularly in the nervous system. Consequently, disrupted mitochondrial function often results in neurodegenerative diseases, in humans and in other mammals. Herein, we determined that the “Turning calves syndrome”, a new hereditary sensorimotor polyneuropathy in the French Rouge-des-Prés cattle breed was due to a single substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. We created a mouse knock-out model and determined that disruption of this gene dramatically disturbed mitochondrial dynamics in various organs that resulted in altered metabolism and early death, indirectly confirming the gene identification in cattle. Moreover, our novel findings extended the range of phenotypes associated with polymorphisms of this gene and help to elucidate the role of SLC25A46 in mitochondrial function.

Published
2017

12. Bacteria isolated from lung modulate asthma susceptibility in mice

Author

Descamps, Delphyne, Noordine, Marie-Louise, Boukadiri, Abdelhak, Mathieu, Elliot, Robert, Véronique, Riffault, Sabine, Lambrecht, Bart, Langella, Philippe, Hammad, Hamida, Remot, Aude, and Thomas, Muriel

Subjects
microbiote, poumon, souris, respiratory tract diseases, asthme
Abstract

Asthma is a chronic, non-curable, multifactorial disease with increasing incidence in industrial countries. This study evaluates the direct contribution of lung microbial components in allergic asthma in mice. Germ-Free and Specific-Pathogen-Free mice display similar susceptibilities to House Dust Mice-induced allergic asthma, indicating that the absence of bacteria confers no protection or increased risk to aeroallergens. In early life, allergic asthma changes the pattern of lung microbiota, and lung bacteria reciprocally modulate aeroallergen responsiveness. Primo-colonizing cultivable strains were screened for their immunoregulatory properties following their isolation from neonatal lungs. Intranasal inoculation of lung bacteria influenced the outcome of allergic asthma development: the strain CNCM I 4970 exacerbated some asthma features whereas the pro-Th1 strain CNCM I 4969 had protective effects. Thus, we confirm that appropriate bacterial lung stimuli during early life are critical for susceptibility to allergic asthma in young adults

Published
2017

13. Structurally related odorant ligands of the olfactory receptor OR51E2 differentially promote metastasis emergence and tumor growth

Author

Leray, Isabelle, Grébert, Denise, Antoine, Sharmilee, Acquistapace, Adrien, Muscat, Adeline, Boukadiri, Abdelhak, Mir, Lluis M., and Sanz, Guenhaël

Subjects
olfactory receptors, odorant ligands, tumor progression, prostate cancer
Abstract

Olfactory receptors are G protein-coupled receptors. Some of them are expressed in tumor cells, such as the OR51E2 receptor overexpressed in LNCaP prostate cancer cells. It is considered a prostate tumor marker. We previously demonstrated that this receptor is able to promote LNCaP cell invasiveness in vitro upon stimulation with its odorant agonist beta-ionone, leading to increased generation of metastases in vivo. In the present study, we show that even a relatively short exposure to beta-ionone is sufficient to promote metastasis emergence. Moreover, alpha-ionone, considered an OR51E2 antagonist, in fact promotes prostate tumor growth in vivo. The combination of alpha-ionone with beta-ionone triggers a higher increase in the total tumor burden than each molecule alone. To support the in vivo results, we demonstrate in vitro that alpha-ionone is a real agonist of OR51E2, mainly sustaining LNCaP cell growth, while beta-ionone mainly promotes cell invasiveness. So, while structurally close, alpha-ionone and beta-ionone appear to induce different cellular effects, both leading to increased tumor aggressiveness. This behaviour could be explained by a different coupling to downstream effectors, as it has been reported for the so-called biased ligands of other G protein-coupled receptors.

Published
2017

14. Hygienic behavior in honey bees and prediction of Varroa non-reproduction in single-drone inseminated (SDI) colonies.

Author

Perrin, Julien, Boukadiri, Abdelhak, Boyard, Pascal, Soubelet, Jean-Baptiste, and Mazoit, Jean Xavier

Abstract

The two standardized assays for testing hygienic behavior in Apis mellifera in the field are the freeze-killed brood (FKB) and the pin-killed brood (PKB) assays. Correlation between the two tests is still in debate. It has been argued that the PKB assay was predictive of Varroa nonreproduction. We measured the agreement between the two methods in two apiaries with 36 and 59 colonies, respectively. The agreement between the two assays was very poor with a 95% limit of agreement greater than 100%. These assays and the SMR (Suppression of Mite Reproduction) trait were also measured in 21 single drone inseminated colonies infested with Varroa and with varying SMR efficacy. A PKB assay result of >46% at 24 h predicted an SMR trait >40% with a sensitivity and a specificity of 0.727 and 0.90, respectively, whereas the FKB assay did not exhibit any predictive value. In conclusion, the PKB and FKB assays are not correlated, but the PKB assay predicted SMR with a good accuracy. [ABSTRACT FROM AUTHOR]

Published
2020
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15. TERT regulation and telomere attrition in a porcine model of melanoma initiation and regression

Author

DESIRABEL, Kévin, Piton, Guillaume, Bruneau, Nicolas, Boukadiri, Abdelhak, Blanc, Fany, Egidy Maskos, Giorgia, Vincent-Naulleau, Silvia, Bourneuf, Emmanuelle, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, iRCM/LREG, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INCa, and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

TERT regulation and telomere attrition in a porcine model of melanoma initiation and regression. Telomere Biology in Health and Disease

Published
2016

16. Preclinical Evaluation of a Novel Epicutaneous Vaccine against Respiratory Syncytial Virus

Author

Hervé, Pierre Louis, Deloizy, Charlotte, Bertho, Nicolas, Chaumeil, Thierry, Renouard, Maud, Bouguyon, Edwige, Descamps, Delphyne, Dubuquoy, Catherine, Dhelft, Véronique, Boukadiri, Abdelhak, Larcher, Thibaut, Guitton, Edouard, Benhamou, Pierre-Henri, Eleouet, Jean Francois, Mondoulet, Lucie, Riffault, Sabine, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Plateforme d'Infectiologie Expérimentale (PFIE), DBV Technologies, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

International audience; In order to be able to put an RSV vaccine onto the market, new vaccination strategies combining scientific and technical innovation need to be explored. In the present project, we describe the development and the non-clinical evaluation of an original epicutaneous RSV vaccine that combines two patented technologies: Viaskin® epicutaneous patches developed by DBV Technologies as a delivery platform, and RSV N-nanorings fused to the F epitope targeted by palivizumab (N-FsII) developed by the French National Institute for Agronomical Research (INRA) as a subunit antigen. We have demonstrated that Viaskin® loaded with a formulation containing N-FsII antigen (Viaskin®- N-FsII) is highly immunogenic in mice and promote a Th1/Th17 oriented immune response. More importantly, Viaskin®-N-FsII epicutaneous vaccine confers a high level of protection against viral replication upon RSV challenge in mice, without exacerbating clinical symptoms. In swine, which provides the best experimental model for the cutaneous passage of drug/antigen in human skin, we have demonstrated that Viaskin®-N-FsII induced a significant RSV N-specific T-cell response. Using this animal model, we have also shown that GFP fluorescent N-nanorings, delivered epicutaneously with Viaskin® patches, are taken up by epidermal Langerhans cells. In conclusion, Viaskin®-N-FsII epicutaneous vaccine seems efficient to protect against RSV infection in animal model. Moreover, since no injection is required and no skin conditioning is needed before application of patches, Viaskin®-N-FsII epicutaneous vaccine would provide a pertinent and safe solution for the vaccination of newborns.

Published
2015

17. Stimulation of olfactory receptors expressed in cancer cells promotes their invasiveness and proloferation, leading ton increased metastasis emergence in vivo

Author

Sanz, Guenhaël, Leray, Isabelle, Grebert, Denise, Antoine, Sharmilee, Acquistapace, Adrien, Boukadiri, Abdelhak, Mir, Lluis M., Neurobiologie de l'olfaction (NBO), Institut National de la Recherche Agronomique (INRA), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and Groupement de Recherche (GDR3545). FRA.

Subjects
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2015

18. Signaling pathways activated during melanoma progression in MeLiM minipigs

Author

Egidy Maskos, Giorgia, Blanc, Fany, Piton, Guillaume, Boukadiri, Abdelhak, Andreoletti, Fabrice, Leplat, Jean Jacques, Bourneuf, Emmanuelle, Vincent-Naulleau, Silvia, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, DSV, IRCM, SREIT, Laboratoire de Radiobiologie et d’Etude du génome, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and INCA - plan cancer 2012

Subjects
[SDV]Life Sciences [q-bio]
Abstract

Signaling pathways activated during melanoma progression in MeLiM minipigs. 19. Meeting of the European Society for Pigment Cell Research

Published
2015

20. Stimulation of the OR51E2 olfactory receptor promotes prostate cancer cell invasiveness, proliferation and metastasis emergence

Author

Sanz, Guenhaël, Leray, Isabelle, Grebert, Denise, Antoine, Sharmilee, Acquistapace, Adrien, Boukadiri, Abdelhak, Mir, Lluis M., Neurobiologie de l'olfaction (NBO), Institut National de la Recherche Agronomique (INRA), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and Groupement de Recherche (GDR 3545). FRA.

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV]Life Sciences [q-bio], [INFO]Computer Science [cs], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2014

22. Rainbow trout (Oncorhynchus mykiss) muscle satellite cells are targets of salmonid alphavirus infection.

Author

Biacchesi, Stéphane, Jouvion, Grégory, Mérour, Emilie, Boukadiri, Abdelhak, Desdouits, Marion, Ozden, Simona, Huerre, Michel, Ceccaldi, Pierre-Emmanuel, and Brémont, Michel

Abstract

Sleeping disease in rainbow trout is characterized by an abnormal swimming behaviour of the fish which stay on their side at the bottom of the tanks. This sign is due to extensive necrosis and atrophy of red skeletal muscle induced by the sleeping disease virus (SDV), also called salmonid alphavirus 2. Infections of humans with arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), are global causes of debilitating musculoskeletal diseases. The mechanisms by which the virus causes these pathologies are poorly understood due to the restrictive availability of animal models capable of reproducing the full spectrum of the disease. Nevertheless, it has been shown that CHIKV exhibits a particular tropism for muscle stem cells also known as satellite cells. Thus, SDV and its host constitute a relevant model to study in details the virus-induced muscle atrophy, the pathophysiological consequences of the infection of a particular cell-type in the skeletal muscle, and the regeneration of the muscle tissue in survivors together with the possible virus persistence. To study a putative SDV tropism for that particular cell type, we established an in vivo and ex vivo rainbow trout model of SDV-induced atrophy of the skeletal muscle. This experimental model allows reproducing the full panel of clinical signs observed during a natural infection since the transmission of the virus is arthropod-borne independent. The virus tropism in the muscle tissue was studied by immunohistochemistry together with the kinetics of the muscle atrophy, and the muscle regeneration post-infection was observed. In parallel, an ex vivo model of SDV infection of rainbow trout satellite cells was developed and virus replication and persistence in that particular cell type was followed up to 73 days post-infection. These results constitute the first observation of a specific SDV tropism for the muscle satellite cells. [ABSTRACT FROM AUTHOR]

Published
2016
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24. CEP250 is Required for Maintaining Centrosome Cohesion in the Germline and Fertility in Male Mice.

Author

Floriot S, Bellutti L, Castille J, Moison P, Messiaen S, Passet B, Boulanger L, Boukadiri A, Tourpin S, Beauvallet C, Vilotte M, Riviere J, Péchoux C, Bertaud M, Vilotte JL, and Livera G

Abstract

Male gametogenesis involves both mitotic divisions to amplify germ cell progenitors that gradually differentiate and meiotic divisions. Centrosomal regulation is essential for both types of divisions, with centrioles remaining tightly paired during the interphase. Here, we generated and characterized the phenotype of mutant mice devoid of Cep250/C-Nap1 , a gene encoding for a docking protein for fibers linking centrioles, and characterized their phenotype. The Cep250 mice presented with no major defects, apart from male infertility due to a reduction in the spermatogonial pool and the meiotic blockade. Spermatogonial stem cells expressing Zbtb16 were not affected, whereas the differentiating spermatogonia were vastly lost. These cells displayed abnormal -/- H2AX-staining, accompanied by an increase in the apoptotic rate. The few germ cells that survived at this stage, entered the meiotic prophase I and were arrested at a pachytene-like stage, likely due to synapsis defects and the unrepaired DNA double-strand breaks. In these cells, centrosomes split up precociously, with γ H2AX-staining, accompanied by an increase in the apoptotic rate. The few germ cells that survived at this stage, entered the meiotic prophase I and were arrested at a pachytene-like stage, likely due to synapsis defects and the unrepaired DNA double-strand breaks. In these cells, centrosomes split up precociously, with γ female mice. Taken together, this study proposes a specific requirement of centrosome cohesion in the male germline, with a crucial role of CEP250 in both differentiating spermatogonia and meiotic spermatocytes.Cep250 -/- female mice. Taken together, this study proposes a specific requirement of centrosome cohesion in the male germline, with a crucial role of CEP250 in both differentiating spermatogonia and meiotic spermatocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Floriot, Bellutti, Castille, Moison, Messiaen, Passet, Boulanger, Boukadiri, Tourpin, Beauvallet, Vilotte, Riviere, Péchoux, Bertaud, Vilotte and Livera.)

Published
2022
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25. Analysis of Polycerate Mutants Reveals the Evolutionary Co-option of HOXD1 for Horn Patterning in Bovidae.

Author

Allais-Bonnet A, Hintermann A, Deloche MC, Cornette R, Bardou P, Naval-Sanchez M, Pinton A, Haruda A, Grohs C, Zakany J, Bigi D, Medugorac I, Putelat O, Greyvenstein O, Hadfield T, Jemaa SB, Bunevski G, Menzi F, Hirter N, Paris JM, Hedges J, Palhiere I, Rupp R, Lenstra JA, Gidney L, Lesur J, Schafberg R, Stache M, Wandhammer MD, Arbogast RM, Guintard C, Blin A, Boukadiri A, Rivière J, Esquerré D, Donnadieu C, Danchin-Burge C, Reich CM, Riley DG, Marle-Koster EV, Cockett N, Hayes BJ, Drögemüller C, Kijas J, Pailhoux E, Tosser-Klopp G, Duboule D, and Capitan A

Subjects
Animals, Biometry, Gene Expression Regulation, Developmental, Goats embryology, Goats metabolism, Homeodomain Proteins metabolism, Male, Mice, Transgenic, Mutation, Sheep embryology, Sheep metabolism, Biological Evolution, Goats genetics, Homeodomain Proteins genetics, Horns, Sheep genetics
Abstract

In the course of evolution, pecorans (i.e., higher ruminants) developed a remarkable diversity of osseous cranial appendages, collectively referred to as "headgear," which likely share the same origin and genetic basis. However, the nature and function of the genetic determinants underlying their number and position remain elusive. Jacob and other rare populations of sheep and goats are characterized by polyceraty, the presence of more than two horns. Here, we characterize distinct POLYCERATE alleles in each species, both associated with defective HOXD1 function. We show that haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Published
2021
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26. Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species.

Author

Bourneuf E, Otz P, Pausch H, Jagannathan V, Michot P, Grohs C, Piton G, Ammermüller S, Deloche MC, Fritz S, Leclerc H, Péchoux C, Boukadiri A, Hozé C, Saintilan R, Créchet F, Mosca M, Segelke D, Guillaume F, Bouet S, Baur A, Vasilescu A, Genestout L, Thomas A, Allais-Bonnet A, Rocha D, Colle MA, Klopp C, Esquerré D, Wurmser C, Flisikowski K, Schwarzenbacher H, Burgstaller J, Brügmann M, Dietschi E, Rudolph N, Freick M, Barbey S, Fayolle G, Danchin-Burge C, Schibler L, Bed'Hom B, Hayes BJ, Daetwyler HD, Fries R, Boichard D, Pin D, Drögemüller C, and Capitan A

Subjects
Animals, Cattle, DNA Mutational Analysis, Disease Models, Animal, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Genomics methods, Humans, Pedigree, Whole Genome Sequencing, Genetic Association Studies, Livestock genetics, Mutation, Phenotype
Abstract

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans.

Published
2017
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27. Bacteria isolated from lung modulate asthma susceptibility in mice.

Author

Remot A, Descamps D, Noordine ML, Boukadiri A, Mathieu E, Robert V, Riffault S, Lambrecht B, Langella P, Hammad H, and Thomas M

Subjects
Allergens, Animals, Bacteria isolation & purification, Disease Susceptibility, Dust immunology, Mice, Mice, Inbred C57BL, Asthma microbiology, Bacterial Physiological Phenomena, Lung microbiology
Abstract

Asthma is a chronic, non-curable, multifactorial disease with increasing incidence in industrial countries. This study evaluates the direct contribution of lung microbial components in allergic asthma in mice. Germ-Free and Specific-Pathogen-Free mice display similar susceptibilities to House Dust Mice-induced allergic asthma, indicating that the absence of bacteria confers no protection or increased risk to aeroallergens. In early life, allergic asthma changes the pattern of lung microbiota, and lung bacteria reciprocally modulate aeroallergen responsiveness. Primo-colonizing cultivable strains were screened for their immunoregulatory properties following their isolation from neonatal lungs. Intranasal inoculation of lung bacteria influenced the outcome of allergic asthma development: the strain CNCM I 4970 exacerbated some asthma features whereas the pro-Th1 strain CNCM I 4969 had protective effects. Thus, we confirm that appropriate bacterial lung stimuli during early life are critical for susceptibility to allergic asthma in young adults.

Published
2017
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28. Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health.

Author

Duchesne A, Vaiman A, Castille J, Beauvallet C, Gaignard P, Floriot S, Rodriguez S, Vilotte M, Boulanger L, Passet B, Albaric O, Guillaume F, Boukadiri A, Richard L, Bertaud M, Timsit E, Guatteo R, Jaffrézic F, Calvel P, Helary L, Mahla R, Esquerré D, Péchoux C, Liuu S, Vallat JM, Boichard D, Slama A, and Vilotte JL

Subjects
Amino Acid Substitution genetics, Animals, Cattle, Humans, Mice, Mitochondria genetics, Mitochondria pathology, Mutation, Phenotype, Polyneuropathies pathology, Polyneuropathies veterinary, Mitochondrial Dynamics genetics, Mitochondrial Proteins genetics, Phosphate Transport Proteins genetics, Polyneuropathies genetics, Proteomics
Abstract

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the "Turning calves syndrome", a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics.

Published
2017
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29. A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading.

Author

Gaillard V, Galloux M, Garcin D, Eléouët JF, Le Goffic R, Larcher T, Rameix-Welti MA, Boukadiri A, Héritier J, Segura JM, Baechler E, Arrell M, Mottet-Osman G, and Nyanguile O

Subjects
Administration, Intranasal, Amino Acid Sequence, Amino Acid Substitution, Animals, Antiviral Agents chemical synthesis, Binding Sites, Female, HeLa Cells, Humans, Mice, Mice, Inbred BALB C, Peptides chemical synthesis, Protein Binding, Protein Conformation, alpha-Helical, Protein Interaction Domains and Motifs, Protein Stability, Proteolysis, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Virus, Human chemistry, Respiratory Syncytial Virus, Human growth & development, Sequence Alignment, Sequence Homology, Amino Acid, Virus Replication drug effects, Antiviral Agents pharmacology, Peptides pharmacology, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus, Human drug effects, Viral Fusion Proteins chemistry, Virus Internalization drug effects
Abstract

Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled-peptide scan across the HR2 domain of the respiratory syncytial virus (RSV) F protein with the aim to identify a minimal domain capable of disrupting the formation of the postfusion six-helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides that display nanomolar potency in HEp-2 cells and are exceptionally robust to proteolytic degradation. By replacing each amino acid of the peptides by an alanine, we found that the substitution of residues 506 to 509, located in a patch of polar contacts between HR2 and HR1, severely affected inhibition. Finally, we show that intranasal delivery of the most potent peptide to BALB/c mice significantly decreased RSV infection in upper and lower respiratory tracts. The discovery of this minimal HR2 sequence as a means for inhibition of RSV infection provides the basis for further medicinal chemistry efforts toward developing RSV fusion antivirals., (Copyright © 2017 Gaillard et al.)

Published
2017
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30. Structurally related odorant ligands of the olfactory receptor OR51E2 differentially promote metastasis emergence and tumor growth.

Author

Sanz G, Leray I, Grébert D, Antoine S, Acquistapace A, Muscat A, Boukadiri A, and Mir LM

Subjects
Animals, Cell Line, Tumor, Cell Movement, Disease Progression, Humans, Male, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Norisoprenoids chemistry, Prostatic Neoplasms metabolism, Up-Regulation, Neoplasm Proteins agonists, Norisoprenoids pharmacology, Prostatic Neoplasms pathology, Receptors, Odorant agonists
Abstract

Olfactory receptors are G protein-coupled receptors. Some of them are expressed in tumor cells, such as the OR51E2 receptor overexpressed in LNCaP prostate cancer cells. It is considered a prostate tumor marker. We previously demonstrated that this receptor is able to promote LNCaP cell invasiveness in vitro upon stimulation with its odorant agonist β-ionone, leading to increased generation of metastases in vivo. In the present study, we show that even a relatively short exposure to β-ionone is sufficient to promote metastasis emergence. Moreover, α-ionone, considered an OR51E2 antagonist, in fact promotes prostate tumor growth in vivo. The combination of α-ionone with β-ionone triggers a higher increase in the total tumor burden than each molecule alone. To support the in vivo results, we demonstrate in vitro that α-ionone is a real agonist of OR51E2, mainly sustaining LNCaP cell growth, while β-ionone mainly promotes cell invasiveness. So, while structurally close, α-ionone and β-ionone appear to induce different cellular effects, both leading to increased tumor aggressiveness. This behaviour could be explained by a different coupling to downstream effectors, as it has been reported for the so-called biased ligands of other G protein-coupled receptors.

Published
2017
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