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8 results on '"MESH: Haploinsufficiency"'

1. LHX2 haploinsufficiency causes a variable neurodevelopmental disorder

Author

Cosima M. Schmid, Anne Gregor, Gregory Costain, Chantal F. Morel, Lauren Massingham, Jennifer Schwab, Chloé Quélin, Marie Faoucher, Julie Kaplan, Rebecca Procopio, Carol J. Saunders, Ana S.A. Cohen, Gabrielle Lemire, Stephanie Sacharow, Anne O’Donnell-Luria, Ranit Jaron Segal, Jessica Kianmahd Shamshoni, Daniela Schweitzer, Darius Ebrahimi-Fakhari, Kristin Monaghan, Timothy Blake Palculict, Melanie P. Napier, Alice Tao, Bertrand Isidor, Kamran Moradkhani, André Reis, Heinrich Sticht, Wendy K. Chung, Christiane Zweier, University of Bern, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
MESH: Autism Spectrum Disorder, NDD, MESH: LIM-Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Intellectual disability, LHX2, MESH: Transcription Factors, ASD, MESH: Intellectual Disability, Neurodevelopmental disorder, Microcephaly, MESH: Haploinsufficiency, 610 Medicine & health, Genetics (clinical), MESH: Neurodevelopmental Disorders
Abstract

PURPOSE LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but has not been clearly linked to neurodevelopmental disorders (NDD) to date. METHODS Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems. RESULTS Affected individuals presented with developmental and/or behavioral abnormalities, autism-spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for two missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction mediating LIM domain, and impaired transcriptional activation by luciferase assay for four missense variants. CONCLUSION We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in nervous system and for variable neurodevelopmental phenotypes.

Published
2023
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2. Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

Author

Michèle Carlier, Lucie Brosse, Pierre L. Roubertoux, Laurent Fasano, Mehdi Metwaly, Paolo Gubellini, Yasmine Belaidouni, Ahmed Fatmi, Pascal Salin, Dorian Chabbert, Jordan Molitor, Xavier Caubit, Lydia Kerkerian-Le Goff, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de psychologie cognitive (LPC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), Gubellini, Paolo, Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique - - TSHZ3inASD2017 - ANR-17-CE16-0030 - AAPG2017 - VALID, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix-Marseille Univ, CNRS, IBDM, UMR7288, Marseille, France, and ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017)

Subjects
striatal cholinergic interneurons, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], MESH: Autistic Disorder, Striatum, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Haploinsufficiency, Biology, MESH: Synapses, Cellular and Molecular Neuroscience, 03 medical and health sciences, Mice, 0302 clinical medicine, stereotyped behaviors, Interneurons, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Conditional gene knockout, medicine, Animals, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, MESH: Mice, Biological Psychiatry, 030304 developmental biology, MESH: Autism Spectrum Disorder, 0303 health sciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, MESH: Interneurons, Autism spectrum disorder (ASD), cortical projection neurons, Psychiatry and Mental health, Electrophysiology, TSHZ3, sociability, medicine.anatomical_structure, nervous system, Autism spectrum disorder, Cerebral cortex, Synapses, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cholinergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Haploinsufficiency, Neuroscience, 030217 neurology & neurosurgery
Abstract

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. We show that in the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABA interneurons, while not in cholinergic interneurons or glial cells. TSHZ3-expressing cells, which are predominantly SCINs in the striatum, represent a low proportion of neurons in the ascending cholinergic projection system. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and plasticity at corticostriatal synapses, with neither cortical neuron loss nor impaired layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

Published
2021
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3. 4q25 microdeletion encompassing PITX2 : A patient presenting with tetralogy of Fallot and dental anomalies without ocular features

Author

P Calvas, S. El Hout, Nicolas Chassaing, C. Zazo Seco, Adeline Vigouroux, Laurence Bouneau, P. Vande Perre, O. Patat, D. Bourgeois, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Toulouse [Toulouse]

Subjects
Male, 0301 basic medicine, Pediatrics, MESH: Epidermal Growth Factor / genetics, Glaucoma, Haploinsufficiency, 030105 genetics & heredity, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Genotype, Eye Abnormalities, PITX2, Child, Genetics (clinical), Tetralogy of Fallot, MESH: Tetralogy of Fallot / pathology, Genetics, 4q25, Eye Diseases, Hereditary, MESH: Tooth Abnormalities / pathology, MESH: Fatty Acid Elongases, General Medicine, MESH: Tooth Abnormalities / genetics, Tetralogy of fallot, Phenotype, Penetrance, Pedigree, 3. Good health, MESH: Acetyltransferases / genetics, Female, MESH: Chromosomes, Human, Pair 4 / genetics, MESH: Haploinsufficiency, Chromosome Deletion, Chromosomes, Human, Pair 4, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Fatty Acid Elongases, MESH: Pedigree, MESH: Chromosome Deletion, MESH: Eye Diseases, Hereditary, Biology, Glutamyl Aminopeptidase, MESH: Phenotype, MESH: Transcription Factors / genetics, 03 medical and health sciences, stomatognathic system, Acetyltransferases, Anterior Eye Segment, medicine, Humans, MESH: Anterior Eye Segment / abnormalities, MESH: Homeodomain Proteins / genetics, Homeodomain Proteins, MESH: Humans, Epidermal Growth Factor, Axenfeld-rieger syndrome, MESH: Glutamyl Aminopeptidase / genetics, Tooth Abnormalities, Point mutation, MESH: Eye Abnormalities / pathology, MESH: Adult, medicine.disease, MESH: Male, eye diseases, stomatognathic diseases, 030104 developmental biology, MESH: Tetralogy of Fallot / genetics, MESH: Eye Abnormalities / genetics, sense organs, MESH: Female, Transcription Factors, MESH: Anterior Eye Segment / pathology
Abstract

International audience; Axenfeld-Rieger syndrome (ARS) is a heterogeneous clinical entity transmitted in an autosomal dominant manner. The main feature, Axenfeld-Rieger Anomaly (ARA), is a malformation of the anterior segment of the eye that can lead to glaucoma and impair vision. Extra-ocular defects have also been reported. Point mutations of FOXC1 and PITX2 are responsible for about 40% of the ARS cases. We describe the phenotype of a patient carrying a deletion encompassing the 4q25 locus containing PITX2 gene. This child presented with a congenital heart defect (Tetralogy of Fallot, TOF) and no signs of ARA. He is the first patient described with TOF and a complete deletion of PITX2 (arr[GRCh37]4q25(110843057-112077858)x1, involving PITX2, EGF, ELOVL6 and ENPEP) inherited from his ARS affected mother. In addition, to our knowledge, he is the first patient reported with no ocular phenotype associated with haploinsufficiency of PITX2. We compare the phenotype and genotype of this patient to those of five other patients carrying 4q25 deletions. Two of these patients were enrolled in the university hospital in Toulouse, while the other three were already documented in DECIPHER. This comparative study suggests both an incomplete penetrance of the ocular malformation pattern in patients carrying PITX2 deletions and a putative association between TOF and PITX2 haploinsufficiency.

Published
2018
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4. Postnatal Tshz3 deletion drives altered corticostriatal function and autism spectrum disorder-like behavior

Author

Michèle Carlier, Pierre L. Roubertoux, Christina Frahm, Laurent Fasano, Mehdi Metwaly, Dany Severac, Paolo Gubellini, Alistair N. Garratt, Bernard Jacq, Ahmed Fatmi, Pascal Salin, Dorian Chabbert, Xavier Caubit, Bianca Habermann, Lydia Kerkerian-Le Goff, Emeric Dubois, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Laboratoire de psychologie cognitive (LPC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique et physiologie du développement (LGPD), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), 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)-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), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-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)

Subjects
Male, 0301 basic medicine, MESH: Chromosomes, Human, Pair 19, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Haploinsufficiency, Striatum, MESH: Mice, Knockout, MESH: Synapses, Mice, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Gene Expression Regulation, Developmental, MESH: Animals, Autism spectrum disorder, MESH: Heterozygote, Mice, Knockout, MESH: Autism Spectrum Disorder, Behavior, Animal, Gene Expression Regulation, Developmental, MESH: Transcription Factors, 3. Good health, TSHZ3, Synaptopathy, Knockout mouse, Cortex, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glutamatergic synapse, MESH: Haploinsufficiency, Chromosome Deletion, Function and Dysfunction of the Nervous System, Heterozygote, MESH: Chromosome Deletion, Biology, behavioral disciplines and activities, 03 medical and health sciences, mental disorders, MESH: Homeodomain Proteins, medicine, Animals, Humans, MESH: Mice, Biological Psychiatry, Homeodomain Proteins, MESH: Humans, Sociability, medicine.disease, MESH: Male, Disease Models, Animal, 030104 developmental biology, Stereotypies, MESH: Gene Deletion, Synapses, Homeobox, MESH: Disease Models, Animal, Chromosomes, Human, Pair 19, Neuroscience, MESH: Female, Gene Deletion, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; BACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3 flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, w50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic syn-apse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

Published
2019
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5. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

Author

Aurélie Poulet, Alexandra Benchoua, Richard Delorme, Laure Chatrousse, Francis Cogé, Delphine Héron, Frédérique Rodet-Amsellem, Millan Mark, Claire Boissart, Thomas Bourgeron, Hélène Darville, Anselme L. Perrier, Caroline Nava, Julie Pernelle, Margot Jarrige, Marc Peschanski, 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)-Généthon, French Biodiversity Agency, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Hydrosystèmes et Bioprocédés (UR HBAN), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Division of General Internal Medicine (DGIM), Université de Genève = University of Geneva (UNIGE), Institut de Recherche Servier, SERVIER, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study has been in part funded by grants from 'Investissements d'Avenir' – (ANR-11-INBS-0009 - INGESTEM – and ANR-11-INBS-0011 - NeurATRIS), the French National Research Agency ANR (ANR-13-SAMA-0006, SynDivAutism), the Laboratory of Excellence GENMED (ANR-10-LABX-0013), the Bettencourt-Schueller Foundation, the Cognacq Jay Foundation, and the Fondamental Foundation. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository, as well as clinical data. NINDS Repository sample numbers corresponding to the samples used are GM 1869., The authors are thankful to I-Stem's HTS platform staff for constant technical support. We thank the cell bank of Pitié-Salpétrière hospital and the Clinical Investigation Center of Robert Debré hospital for assistance with patient recruitment, information, sampling and fibroblast preparation. H.D. received a PhD grant from Servier's Laboratories. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon)., ANR-11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), d'Eggis, Gilles, Infrastructures - INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES - - INGESTEM2011 - ANR-11-INBS-0009 - INBS - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], 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)-CHU Pitié-Salpêtrière [APHP], University of Geneva [Switzerland], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], ANR-11-INBS-0009/11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011/11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, GAS, Global Assessment Scale, 0301 basic medicine, VPA, valproic acid, Autism Spectrum Disorder, Cellular differentiation, Autism, Human Embryonic Stem Cells, Drug repurposing, MESH: Neurons, lcsh:Medicine, hESC, human embryonic stem cells, Haploinsufficiency, Severity of Illness Index, RPM, Raven's progressive matrices, MESH: Nerve Tissue Proteins, MESH: Neuronal Plasticity, Induced pluripotent stem cell, SHANK3, Cells, Cultured, ASD, autism spectrum disorders, Neurons, ADOS, Autism Diagnosis Observational Scale, Genetics, MESH: Autism Spectrum Disorder, lcsh:R5-920, Neuronal Plasticity, PPVT, Peabody Picture Vocabulary Test, PSC, pluripotent stem cells, Cell Differentiation, General Medicine, Neural stem cell, 3. Good health, Drug repositioning, Phenotype, Autism spectrum disorder, MESH: Pluripotent Stem Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Haploinsufficiency, lcsh:Medicine (General), Research Paper, MESH: Cells, Cultured, Pluripotent Stem Cells, MESH: Cell Differentiation, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Nerve Tissue Proteins, ADHD, Attention Deficit Hyperactive Disorder, Lithium, SHANK3, SH3 and multiple ankyrin repeat domains 3, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, iPSC, induced pluripotent stem cells, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, High throughput screening, MESH: Severity of Illness Index, medicine, Humans, NSC, neural stem cells, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], HTS, high throughput screening, MESH: RNA, Messenger, Valproate, MESH: Humans, MESH: Lithium, business.industry, Valproic Acid, MESH: Transcriptome, lcsh:R, MESH: Human Embryonic Stem Cells, medicine.disease, FDA, Food and Drug Administration, Embryonic stem cell, MESH: Male, DMSO, dimethylsulfoxyde, PPIA, Peptidylprolyl Isomerase A, 030104 developmental biology, SRS, Social Responsiveness Scale, Transcriptome, business, Neuroscience, MESH: Valproic Acid
Abstract

Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments., Highlights • Human neurons were used to screen for compounds correcting symptoms associated with SHANK3 haploinsufficiency syndrome. • Screening criteria were the ability to increase SHANK3 expression and to increase glutamatergic transmission. • Selected hit compounds were then validated using neurons differentiated from individuals with SHANK3 disrupting mutations. • Lithium was selected and delivered to one of SHANK3 patient showing encouraging positive clinical outcomes after one year. The clinical heterogeneity between individuals affected by autism makes it difficult to anticipate the effectiveness of a treatment. Furthermore, clinical practice lacks biological tools to help make such decisions. Here we use neurons, produced from pluripotent stem cells derived from patients affected by SHANK3 haploinsufficiency syndrome, to test the efficiency of therapeutic compounds. We screened the biological activity of more than 200 compounds on SHANK3 expression. Lithium was ultimately selected and delivered to one patient with a SHANK3-disruptive mutation. This resulted in a positive outcome, as determined by improved autistic core symptoms, thus supporting the usefulness of this type of predictive approach.

Published
2016
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6. Sumoylation controls host anti‐bacterial response to the gut invasive pathogen Shigella flexneri

Author

Alexandra Andrieux, Filip Golebiowski, Sabrina Fritah, Philippe J. Sansonetti, Ronald T. Hay, Joëlle Mounier, Nouara Lhocine, Anne Dejean, Grégory Jouvion, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, Centre de Recherche Public de la Santé, Pathogénie Microbienne Moléculaire, University of Dundee, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], This work was supported by grants from LNCC (Equipe labellisée), Odyssey-RE, INCa, ANR and ERC. S.F. was supported by RUBICON and Sidaction., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), and Cheriet Rauline, Samia

Subjects
MESH: Inflammation, MESH: Shigella flexneri, [SDV]Life Sciences [q-bio], SUMO protein, Haploinsufficiency, medicine.disease_cause, Biochemistry, Shigella flexneri, Mice, 0302 clinical medicine, Ubc9, Shigella, MESH: Animals, Pathogen, 0303 health sciences, biology, MESH: Sumoylation, Intestinal epithelium, Intestines, [SDV] Life Sciences [q-bio], MESH: Epithelial Cells, Host-Pathogen Interactions, Small Ubiquitin-Related Modifier Proteins, MESH: Haploinsufficiency, medicine.symptom, transcription, MESH: Intestines, Shigellosis, MESH: Dysentery, Bacillary, Inflammation, Microbiology, 03 medical and health sciences, proteomics, Genetics, medicine, Animals, Humans, Molecular Biology, MESH: Mice, 030304 developmental biology, Dysentery, Bacillary, Intestinal permeability, MESH: Humans, Scientific Reports, MESH: Host-Pathogen Interactions, Sumoylation, Epithelial Cells, medicine.disease, biology.organism_classification, MESH: Small Ubiquitin-Related Modifier Proteins, SUMO, inflammation, MESH: Protein Processing, Post-Translational, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

International audience; Shigella flexneri, the etiological agent of bacillary dysentery, invades the human colonic epithelium and causes its massive inflammatory destruction. Little is known about the post-translational modifications implicated in regulating the host defense pathway against Shigella. Here, we show that SUMO-2 impairs Shigella invasion of epithelial cells in vitro. Using mice haploinsufficient for the SUMO E2 enzyme, we found that sumoylation regulates intestinal permeability and is required to restrict epithelial invasion and control mucosal inflammation. Quantitative proteomics reveals that Shigella infection alters the sumoylation status of a restricted set of transcriptional regulators involved in intestinal functions and inflammation. Consistent with this, sumoylation restricts the pro-inflammatory transcriptional response of Shigella-infected guts. Altogether, our results show that the SUMO pathway is an essential component of host innate protection, as it reduces the efficiency of two key steps of shigellosis: invasion and inflammatory destruction of the intestinal epithelium.

Published
2014
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7. Haploinsufficiency of COQ4 causes coenzyme Q10 deficiency

Author

Michio Hirano, Rafael Artuch, Eva Trevisson, Geppo Sartori, Maria Andrea Desbats, Salvatore DiMauro, Sabrina Sacconi, Caterina Agosto, Catarina M. Quinzii, Plácido Navas, Matteo Cassina, Vanessa Pertegato, Alberto Casarin, Leonardo Salviati, Orsetta Zuffardi, María Angeles Hernández, Carlos Santos-Ocaña, Luigi Memo, Mara Doimo, Fondazione Cassa di Risparmio di Padova e Rovigo, Fondazione Telethon, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Università degli Studi di Padova, Instituto de Salud Carlos III, Fondazione Cariplo, National Institutes of Health (US), Ministero della Salute, Dpt. of Pediatrics, Universita degli Studi di Padova, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Cytogenetics, Human Genetics, Instituto de Salud Carlos III [Madrid] (ISC), Cell Biology, and Universidad Pablo de Olavide [Sevilla] (UPO)

Subjects
Male, Transcription, Genetic, Ubiquinone, Haploinsufficiency, chemistry.chemical_compound, 0302 clinical medicine, COQ6, MESH: Ubiquinone, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Comparative Genomic Hybridization, 0303 health sciences, Gene knockdown, food and beverages, MESH: Mitochondrial Proteins, MESH: Saccharomyces cerevisiae, 3. Good health, Child, Preschool, MESH: Haploinsufficiency, Coenzyme Q10 deficiency, MESH: Electron Transport Chain Complex Proteins, medicine.medical_specialty, MESH: Abnormalities, Multiple, Saccharomyces cerevisiae, Biology, Article, Electron Transport, Mitochondrial Proteins, 03 medical and health sciences, MESH: Cell Proliferation, Molecular genetics, Genetics, medicine, Humans, Abnormalities, Multiple, MESH: Electron Transport, Gene, Cell Proliferation, 030304 developmental biology, Coenzyme Q10, MESH: Humans, Cell growth, MESH: Transcription, Genetic, MESH: Child, Preschool, Fibroblasts, medicine.disease, Molecular biology, MESH: Male, MESH: Comparative Genomic Hybridization, Electron Transport Chain Complex Proteins, chemistry, MESH: Fibroblasts, MESH: HeLa Cells, 030217 neurology & neurosurgery, HeLa Cells
Abstract

PMCID: PMC3983946.-- et al., [Background]: COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q10 (CoQ10). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ10 deficiency. [Methods]: A complete molecular and biochemical characterisation of the patient's fibroblasts and of a yeast model were performed. [Results]: The study found reduced COQ4 expression (48% of controls), CoQ10 content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ10 to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ10. Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ10 biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ10 supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued. [Conclusion]: Mutations of COQ4 should be searched for in patients with CoQ10 deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ10 deficiency, as they could benefit from supplementation., This work was supported by Telethon Italy grant no GGP09207, CARIPARO foundation, the Spanish Ministerio de Sanidad (FIS) grant no PI 08/0500, University of Padova grant no 2010-CPDA102953, Italian Ministry of Health grant no GR-2009-1578914, National Institute of Health grant nos 1R01HD057543-01 and HD 32062, and Cariplo Foundation grant no 2007.5197.

Published
2012
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8. WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice

Author

Sonia Bergaya, Xavier Jeunemaitre, Juliette Hadchouel, Gervaise Loirand, Marc Rio, Jean-Michel Achard, Brigitte Escoubet, Daniel Henrion, Sébastien Faure, Véronique Baudrie, Philippe Bonnin, Département de physiologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Architecture, Ville, Urbanisme, Environnement (LAVUE), École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Ministère de la Culture (MC)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Nanterre (UPN)-Ministère de la Culture (MC)-Université Paris 8 Vincennes-Saint-Denis (UP8)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris 8 Vincennes-Saint-Denis (UP8)-École nationale supérieure d'architecture de Paris-La Villette (ENSAPLV), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Nanterre (UPN)-École nationale supérieure d'architecture de Paris Val-de-Seine (ENSA PVDS)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Angers, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Architecture, Ville, Urbanisme, Environnement ( LAVUE ), Université Paris 8 Vincennes-Saint-Denis ( UP8 ) -Université Paris Nanterre ( UPN ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Neurovasculaire et Mitochondriale Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pharmacologie des Immunosuppresseurs et de la Transplantation ( PIST ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), and Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
Male, MESH: Phenylephrine, MESH : Carotid Arteries, Blood Pressure, MESH : Blotting, Western, MESH : Mice, 129 Strain, Mice, Phenylephrine, MESH : Phosphorylation, 0302 clinical medicine, MESH: Animals, 0303 health sciences, MESH : Vasoconstrictor Agents, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Blood Pressure, MESH : Norepinephrine, MESH: Vasoconstriction, MESH: Haploinsufficiency, MESH : Vasoconstriction, MESH : Haploinsufficiency, medicine.medical_specialty, MESH: Aorta, Thoracic, Blotting, Western, MESH : Solute Carrier Family 12, Member 2, MESH: Protein-Serine-Threonine Kinases, MESH : Angiotensin II, 03 medical and health sciences, MESH: Mice, 129 Strain, MESH: Blotting, Western, Dose-Response Relationship, Drug, MESH: Phosphorylation, MESH: Sodium-Potassium-Chloride Symporters, medicine.disease, Mice, Inbred C57BL, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, Endocrinology, Blood pressure, Vasoconstriction, MESH: Adrenergic alpha-1 Receptor Agonists, MESH: Female, MESH: Receptors, Adrenergic, alpha-1, Aorta, Thoracic, MESH : Dose-Response Relationship, Drug, Haploinsufficiency, 030204 cardiovascular system & hematology, Essential hypertension, MESH: Mice, Knockout, MESH: Dose-Response Relationship, Drug, Norepinephrine, WNK Lysine-Deficient Protein Kinase 1, MESH: Reverse Transcriptase Polymerase Chain Reaction, Solute Carrier Family 12, Member 2, Vasoconstrictor Agents, MESH : Female, Phosphorylation, Receptor, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Reabsorption, Angiotensin II, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Carotid Arteries, Female, MESH: Solute Carrier Family 12, Member 2, MESH: Angiotensin II, medicine.symptom, Signal transduction, MESH : Sodium-Potassium-Chloride Symporters, MESH : Adrenergic alpha-1 Receptor Agonists, MESH : Protein-Serine-Threonine Kinases, Mice, 129 Strain, MESH : Receptors, Adrenergic, alpha-1, Sodium-Potassium-Chloride Symporters, MESH : Male, Myogenic contraction, MESH : Mice, Inbred C57BL, In Vitro Techniques, Protein Serine-Threonine Kinases, Biology, Minor Histocompatibility Antigens, MESH: Vasoconstrictor Agents, MESH: Mice, Inbred C57BL, Receptors, Adrenergic, alpha-1, Internal medicine, MESH: Norepinephrine, MESH : Mice, MESH : Blood Pressure, Internal Medicine, medicine, Animals, MESH: Mice, MESH : Aorta, Thoracic, 030304 developmental biology, MESH: Carotid Arteries, MESH: Male, MESH : Phenylephrine, MESH : Mice, Knockout, Adrenergic alpha-1 Receptor Agonists, MESH : Animals, Ex vivo
Abstract

Gain-of-function mutations in the human WNK1 ( with-no-lysine[K]1 ) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1 +/− haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1 +/− mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following α 1 -adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1 +/− arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na + -K + -2Cl − cotransporter 1) in Wnk1 +/− arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to α 1 -adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking α 1 -adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension.

Published
2011
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