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33 results on '"Jean-Pierre Hardelin"'

1. Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety

Author: Stéphanie Pons, Fabio Marti, Clément Solié, Jean-François Fiancette, Véronique Deroche-Gamonet, Joachim Jehl, Deniz Dalkara, Alexandre Mourot, Jean-Pierre Hardelin, Steve Didienne, Tinaïg Le Borgne, Stefania Tolu, Lauren M. Reynolds, B. Hannesse, Ines Centeno, Uwe Maskos, Sébastien Valverde, Maxime Come, Philippe Faure, Claire Nguyen, Sarah Mondoloni, Romain Durand-de Cuttoli, Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-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), Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Centre national de la recherche scientifique (CNRS, UMR 8246), Institut national de la santé et de la recherche médicale (Inserm, U1130), Fondation pour la recherche médicale (FRM, DEQ2013326488 to P.F., FDT201904008060 to S.M., ECO201806006688 to J.J., and SPF202005011922 to C.S.), French National Cancer Institute grants TABAC-16-022 and TABAC-19-020 (to P.F.), French state funds managed by Agence Nationale de la Recherche (ANR-16 Nicostress to P.F., ANR-19 Vampire to F.M.), and LabEx Bio-Psy (to P.F. and a doctoral fellowship to C.N.). L.M.R. was supported by a National Institute on Drug Abuse (NIDA)-Inserm Postdoctoral Drug Abuse Research Fellowship. P.F. and U.M. are members of LabEx Bio-Psy., ANR-16-CE16-0020,nicostress,Réseaux neuronaux sous-tendant l'intéraction entre stress et nicotine dans le cadre des troubles psychiatriques(2016), ANR-19-CE16-0001,VAmPiRe,Effets opposés de la nicotine sur des neurones dopaminergiques distincts : un rôle spécifique de la voie VTA-Amygdala dans le renforcement(2019), ANR-11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011), Moheb, Tara, Réseaux neuronaux sous-tendant l'intéraction entre stress et nicotine dans le cadre des troubles psychiatriques - - nicostress2016 - ANR-16-CE16-0020 - AAPG2016 - VALID, Effets opposés de la nicotine sur des neurones dopaminergiques distincts : un rôle spécifique de la voie VTA-Amygdala dans le renforcement - - VAmPiRe2019 - ANR-19-CE16-0001 - AAPG2019 - VALID, Laboratoire de Psychiatrie Biologique - - BIOPSY2011 - ANR-11-LABX-0035 - LABX - VALID, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, nucleus accumbens, Dopamine, Anxiety, Receptors, Nicotinic, dopamine circuits, MESH: Nicotine, Nicotine, Mice, [SCCO]Cognitive science, 0302 clinical medicine, MESH: Amygdala, Neural Pathways, MESH: Dopaminergic Neurons, MESH: Animals, Nicotinic Agonists, 0303 health sciences, Chemistry, General Neuroscience, musculoskeletal, neural, and ocular physiology, amygdala, Ventral tegmental area, Nicotinic agonist, medicine.anatomical_structure, MESH: Receptors, Nicotinic, addiction, MESH: Nucleus Accumbens, Reinforcement, Psychology, psychological phenomena and processes, medicine.drug, ventral tegmental area, MESH: Dopamine, Nucleus accumbens, Optogenetics, Amygdala, 03 medical and health sciences, mental disorders, MESH: Nicotinic Agonists, medicine, Animals, optogenetics, MESH: Mice, 030304 developmental biology, MESH: Anxiety, Dopaminergic Neurons, MESH: Neural Pathways, [SCCO] Cognitive science, MESH: Male, Anxiogenic, nervous system, juxtacellular recordings, MESH: Ventral Tegmental Area, nicotinic acetylcholine receptors, Neuroscience, MESH: Reinforcement, Psychology, 030217 neurology & neurosurgery, nicotine
Abstract: International audience; Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on β2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.
Published: 2021
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2. Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane

Author: Paul Avan, Sébastien Le Gal, Vincent Michel, Typhaine Dupont, Elisabeth Verpy, Christine Petit, Jean-Pierre Hardelin, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the European Commission (ERC-2011-ADG-294570, to C.P.), Banque Nationale de Paris Paribas, Fondation pour l’Audition, Stiftung Lebenshilfewerk, and by French state funds managed by the Agence Nationale de la Recherche within the 'Investissement d’Avenir' program (ANR-15-RHUS-0001 and LabEx LifeSenses ANR-10-LABX-65) and ANR-16-CE13-0015-02., We thank Jacques Boutet de Monvel for helpful comments on the manuscript, and Jérémie Chatel-Poujade, Isabelle Perfettini, and Céline Trébeau for technical assistance., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Tectorial Membrane, Tectorial membrane, Hearing Loss, Sensorineural, Stereocilia (inner ear), Mechanoelectrical transduction, horizontal top connector, Deafness, Stereocilia, Hair Cells, Vestibular, Mice, 03 medical and health sciences, 0302 clinical medicine, otoacoustic emission, otorhinolaryngologic diseases, medicine, Animals, Genetic Predisposition to Disease, air bundle link, Outer hair cells, tectorial membrane-attachment crown, Cochlea, 030304 developmental biology, outer hair cell, Mice, Knockout, 0303 health sciences, Membrane Glycoproteins, Multidisciplinary, Chemistry, [SCCO.NEUR]Cognitive science/Neuroscience, Biological Sciences, Cell biology, Sensory epithelium, Hair Cells, Auditory, Outer, medicine.anatomical_structure, Intercellular Signaling Peptides and Proteins, sense organs, Hair cell, 030217 neurology & neurosurgery
Abstract: International audience; The function of outer hair cells (OHCs), the mechanical actuators of the cochlea, involves the anchoring of their tallest stereocilia in the tectorial membrane (TM), an acellular structure overlying the sensory epithelium. Otogelin and otogelin-like are TM proteins related to secreted epithelial mucins. Defects in either cause the DFNB18B and DFNB84B genetic forms of deafness, respectively, both characterized by congenital mild-to-moderate hearing impairment. We show here that mutant mice lacking otogelin or otogelin-like have a marked OHC dysfunction, with almost no acoustic distortion products despite the persistence of some mechanoelectrical transduction. In both mutants, these cells lack the horizontal top connectors, which are fibrous links joining adjacent stereocilia, and the TM-attachment crowns coupling the tallest stereocilia to the TM. These defects are consistent with the previously unrecognized presence of otogelin and otogelin-like in the OHC hair bundle. The defective hair bundle cohesiveness and the absence of stereociliary imprints in the TM observed in these mice have also been observed in mutant mice lacking stereocilin, a model of the DFNB16 genetic form of deafness, also characterized by congenital mild-to-moderate hearing impairment. We show that the localizations of stereocilin, otogelin, and otogelin-like in the hair bundle are interdependent, indicating that these proteins interact to form the horizontal top connectors and the TM-attachment crowns. We therefore suggest that these 2 OHC-specific structures have shared mechanical properties mediating reaction forces to sound-induced shearing motion and contributing to the coordinated displacement of stereocilia.
Published: 2019
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3. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

Author: Omar Akil, Saaid Safieddine, Jacques Boutet de Monvel, Charlotte Calvet, Frank M. Dyka, Ghizlene Lahlou, Sylvie Nouaille, Jean-Pierre Hardelin, Paul Avan, Alice Emptoz, Christine Petit, William W. Hauswirth, Lawrence R. Lustig, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Florida [Gainesville] (UF), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Columbia University Medical Center (CUMC), Columbia University [New York], This work was supported by the Hearing Research Incorporation (O.A.), Fondation pour la Recherche Médicale (A.E.), Région Ile de France (DIM Thérapie génique), the European Union Seventh Framework Programme under the Grant Agreement HEALTH-F2-2010-242013 (TREAT RUSH), the French government funds managed by Agence Nationale de la Recherche (EargenCure), and LabEx Lifesenses (ANR-10-BNP Paribas Foundation, FAUN Stiftung, LHW Stiftung, and Mrs. Errera Hoechstetter)., ANR-17-CE18-0027,EARGENCURE,Restauration, par thérapie génique, de l'audition et de l'équilibre chez des souris modèles de surdités et troubles vestibulaires humains(2017), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Medical Sciences, [SDV]Life Sciences [q-bio], Genetic enhancement, Genetic Vectors, Mutant, Mice, Transgenic, Biology, law.invention, Mice, otoferlin, 03 medical and health sciences, 0302 clinical medicine, law, deafness, Complementary DNA, otorhinolaryngologic diseases, DFNB9, Animals, Humans, Coding region, Vector (molecular biology), Gene, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Membrane Proteins, Genetic Therapy, Biological Sciences, Dependovirus, gene therapy, Phenotype, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, Recombinant DNA, dual AAV, 030217 neurology & neurosurgery
Abstract: Significance In humans, inner ear development is completed in utero, with hearing onset at ∼20 weeks of gestation. However, genetic forms of congenital deafness are typically diagnosed during the neonatal period. Gene therapy approaches in animal models should therefore be tested after the period of hearing onset, to determine whether they can reverse an existing deafness phenotype. Here, we used a mouse model of DFNB9, a human deafness form accounting for 2–8% of all cases of congenital genetic deafness. We show that local gene therapy in the mutant mice not only prevents deafness when administered to immature hearing organs, but also durably restores hearing when administered at a mature stage, raising hopes for future gene therapy trials in DFNB9 patients., Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5′ and the other the 3′ portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea of Otof−/− mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5′ and 3′ cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.
Published: 2019
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4. Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells

Author: Elise Pepermans, Vincent Michel, Alain Aghaie, Jean-Pierre Hardelin, Amel Bahloul, Sylvie Nouaille, Isabelle Perfettini, Patrick England, Christine Petit, Jacques Boutet de Monvel, Florent Delhommel, Nicolas Wolff, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Structural Biology (Neuherberg), Helmholtz-Zentrum München (HZM), Récepteurs Canaux - Channel Receptors, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Stanford University, This work was supported by Institut Pasteur PTR program No.483, by Agence Nationale de la Recherche (ANR) within the framework of the Investissements d'Avenir program (ANR‐15‐RHUS‐0001), Laboratoire d'excellence (LabEx) Lifesenses (ANR‐10‐LABX‐65), ANR‐11‐IDEX‐0004‐02, ANR‐11‐BSV5‐0011, and grants from Fondation Agir pour l'Audition, the BNP Paribas Foundation, the FAUN Stiftung, the LHW‐Stiftung and Mrs. Errera Hoechstetter., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-11-BSV5-0011,EARMEC,Propriétés mécaniques, actives et passives, de la touffe ciliaire des cellules mécano-sensorielles ciliées le long de l'axe tonotopique de la cochlée des mammifères.(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Helmholtz Zentrum München = German Research Center for Environmental Health, Collège de France - Chaire Génétique et physiologie cellulaire, Gestionnaire, HAL Sorbonne Université 5, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, and BLANC - Propriétés mécaniques, actives et passives, de la touffe ciliaire des cellules mécano-sensorielles ciliées le long de l'axe tonotopique de la cochlée des mammifères. - - EARMEC2011 - ANR-11-BSV5-0011 - BLANC - VALID
Subjects: Scaffold protein, Male, Stereocilia (inner ear), PDZ domain, lcsh:Medicine, Cadherin Related Proteins, Diseases, [SDV.GEN] Life Sciences [q-bio]/Genetics, Mechanotransduction, Cellular, Biochemistry, Article, Stereocilia, 03 medical and health sciences, Mice, 0302 clinical medicine, CDH23, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, Protein Isoforms, Protein Precursors, Cytoskeleton, lcsh:Science, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Chemistry, lcsh:R, Membrane Proteins, Cell Differentiation, Actin cytoskeleton, Cadherins, Cell biology, Cochlea, Mice, Inbred C57BL, medicine.anatomical_structure, Microscopy, Electron, Scanning, lcsh:Q, Female, Hair cell, sense organs, Engineering sciences. Technology, 030217 neurology & neurosurgery, PCDH15, Neuroscience
Abstract: International audience; The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction. It is formed by three rows of stiff microvilli-like protrusions of graduated heights, the short, middle-sized, and tall stereocilia. In developing and mature sensory hair cells, stereocilia are connected to each other by various types of fibrous links. Two unconventional cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23), form the tip-links, whose tension gates the hair cell mechanoelectrical transduction channels. These proteins also form transient lateral links connecting neighboring stereocilia during hair bundle morphogenesis. The proteins involved in anchoring these diverse links to the stereocilia dense actin cytoskeleton remain largely unknown. We show that the long isoform of whirlin (L-whirlin), a PDZ domain-containing submembrane scaffold protein, is present at the tips of the tall stereocilia in mature hair cells, together with PCDH15 isoforms CD1 and CD2; L-whirlin localization to the ankle-link region in developing hair bundles moreover depends on the presence of PCDH15-CD1 also localizing there. We further demonstrate that L-whirlin binds to PCDH15 and CDH23 with moderate-to-high affinities in vitro. From these results, we suggest that L-whirlin is part of the molecular complexes bridging PCDH15-, and possibly CDH23-containing lateral links to the cytoskeleton in immature and mature stereocilia. The sensory cells of the cochlea (inner and outer hair cells) convert acoustic waves into receptor potentials by the process of mechanoelectrical transduction (MET) 1,2. This process takes place in the hair bundle, a mechanosensi-tive antenna formed by thick and stiff microvilli-like protrusions called stereocilia, organized in three rows of graduated height (i.e., short, middle-sized, and tall stereocilia) at the apical surface of the hair cells. Stereocilia are connected, within and between rows, by various types of fibrous links, expressed both in the developing and the mature cochlea. According to the current view of the MET process, cationic transducer channels located at the tips of short and middle-sized stereocilia 3 are gated by the sound-evoked periodic tension of the tip link, an open
Published: 2019
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5. Mutations in CDC14A , Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness

Author: Zied Riahi, Christine Petit, Sébastien Chardenoux, Hala El Hachmi, Crystel Bonnet, Sedigheh Delmaghani, Philippe Herbomel, Isabelle Perfettini, Yosra Bouyacoub, Ahmed Houmeida, Jean-Pierre Hardelin, Asadollah Aghaie, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Laboratoire de Biochimie et Biologie Moléculaire [Nouakchott], Faculté des Sciences et Techniques [Nouakchott, Mauritania], Macrophages et Développement de l’Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported by the French state program 'Investissements d’Avenir' (ANR-10-LABX-65), BNP Paribas, and Bucodes SurdiFrance., Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: Adult, Male, 0301 basic medicine, Morpholino, Hearing Loss, Sensorineural, Nonsense mutation, Fluorescent Antibody Technique, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Severity of Illness Index, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Report, Ciliogenesis, Hair Cells, Auditory, otorhinolaryngologic diseases, Genetics, medicine, Animals, Humans, Genetics(clinical), Cilia, Nonsyndromic deafness, Zebrafish, Genetics (clinical), Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cilium, Middle Aged, Kinocilium, medicine.disease, biology.organism_classification, Molecular biology, Phosphoric Monoester Hydrolases, Pedigree, 030104 developmental biology, medicine.anatomical_structure, Larva, Mutation, Female, sense organs, Hair cell, Protein Tyrosine Phosphatases, 030217 neurology & neurosurgery
Abstract: International audience; By genetic linkage analysis in a large consanguineous Iranian family with eleven individuals affected by severe to profound congenital deafness, we were able to define a 2.8 Mb critical interval (at chromosome 1p21.2-1p21.1) for an autosomal-recessive nonsyndromic deafness locus (DFNB). Whole-exome sequencing allowed us to identify a CDC14A biallelic nonsense mutation, c.1126C>T (p.Arg376∗), which was present in the eight clinically affected individuals still alive. Subsequent screening of 115 unrelated individuals affected by severe or profound congenital deafness of unknown genetic cause led us to identify another CDC14A biallelic nonsense mutation, c.1015C>T (p.Arg339∗), in an individual originating from Mauritania. CDC14A encodes a protein tyrosine phosphatase. Immunofluorescence analysis of the protein distribution in the mouse inner ear showed a strong labeling of the hair cells’ kinocilia. By using a morpholino strategy to knockdown cdc14a in zebrafish larvae, we found that the length of the kinocilia was reduced in inner-ear hair cells. Therefore, deafness caused by loss-of-function mutations in CDC14A probably arises from a morphogenetic defect of the auditory sensory cells’ hair bundles, whose differentiation critically depends on the proper growth of their kinocilium.
Published: 2016
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6. Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Author: Alice, Emptoz, Vincent, Michel, Andrea, Lelli, Omar, Akil, Jacques, Boutet de Monvel, Ghizlene, Lahlou, Anaïs, Meyer, Typhaine, Dupont, Sylvie, Nouaille, Elody, Ey, Filipa, Franca de Barros, Mathieu, Beraneck, Didier, Dulon, Jean-Pierre, Hardelin, Lawrence, Lustig, Paul, Avan, Christine, Petit, Saaid, Safieddine, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), University of California [San Francisco] (UC San Francisco), University of California (UC), 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), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Columbia University [New York], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by Fondation pour la Recherche Médicale (A.E.), the European UnionSeventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the European Commission (ERC-2011-ADG_294570), French state funds managed by Agence Nationale de la Recherche within theInvestissements d’Avenir Programme (ANR-15-RHUS-0001), LabEx Lifesenses(ANR-10-LABX-65), and grants from the BNP Paribas Foundation, the FAUN-Stiftung, the LHW-Stiftung, and Errera Hoechstetter., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), CHAUVET, Laurence, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, Chaire Génétique et physiologie cellulaire, University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: DNA, Complementary, [SDV]Life Sciences [q-bio], Genetic Vectors, Nerve Tissue Proteins, Mice, Hair Cells, Auditory, Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, gene, mouse, Mice, Knockout, therapy, balance, Genetic Therapy, Dependovirus, Biological Sciences, [SDV] Life Sciences [q-bio], Disease Models, Animal, Animals, Newborn, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Microscopy, Electron, Scanning, Vestibule, Labyrinth, sense organs, Usher Syndromes, Usher
Abstract: International audience; Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensi-tivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected. gene | therapy | balance | mouse | Usher
Published: 2017
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7. Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice

Author: Jean-Pierre Hardelin, Corinne Fouveaut, Catherine Dodé, Fabrice Ango, Séverine Marcos, Nelly Pitteloud, Xavier Rovira, Carine Monnier, Universitat de Vic - Universitat Central de Catalunya. Grup de recerca en Reparació i Regeneració Tissular (TR2Lab), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut Pasteur [Paris], Agence Nationale pour la Recherche (grant number ANR-14-CE12-0015 to S.M., C.M., F.A., C.D., and J.-P.H.), We thank the patients for their contribution to the study. We also thank the animal platform (CRP2, CNRS UMS3612, Inserm US25, Paris-Descartes University) for housing of the mice., ANR-14-CE12-0015,RoSes and GnRH,La signalisation cellulaire par les sémaphorines dans le contrôle neuroendocrinien de la reproduction(2014), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and CHU Cochin [AP-HP]
Subjects: Male, 0301 basic medicine, Olfactory system, Kallmann syndrome, [SDV]Life Sciences [q-bio], Semaphorins, Gonadotropin-releasing hormone, medicine.disease_cause, Gonadotropin-Releasing Hormone, Mice, 0302 clinical medicine, Cell Movement, Genetics (clinical), Neurons, Mutation, Genètica humana, biology, Reproduction, Oligogenic Inheritance, General Medicine, Olfactory Bulb, 3. Good health, Female, Síndrome de Kallmann, Signal Transduction, Adult, Heterozygote, medicine.medical_specialty, Cell signaling, Hypothalamus, Nerve Tissue Proteins, Receptors, Cell Surface, 03 medical and health sciences, Neuroendocrine Cells, Semaphorin, Internal medicine, Genetics, medicine, Animals, Humans, Molecular Biology, Hypogonadism, Plexin, Semaphorin-3A, Kallmann Syndrome, medicine.disease, 030104 developmental biology, Endocrinology, biology.protein, 030217 neurology & neurosurgery
Abstract: The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the disease pathogenesis. Here, we report that the embryonic phenotype of Plxna1-/- mutant mice lacking plexin-A1 (a major receptor of class 3 semaphorins), though not fully penetrant, resembles that of Kallmann syndrome fetuses. Pathohistological analysis indeed showed a strongly abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the hypothalamic brain region in some of the mutant mice, which resulted in reduced fertility in adult males. We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. Most of these mutations are predicted to affect plexin-A1 stability or signaling activity based on predictive algorithms and a structural model of the protein. Moreover, in vitro experiments allowed us to show the existence of deleterious effects of eight mutations (including a transcript splicing defect), none of which are expected to result in a complete loss of protein synthesis, targeting, or signaling activity, though. Our findings indicate that signaling insufficiency through plexin-A1 can contribute to the pathogenesis of Kallmann syndrome, and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
Published: 2017
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8. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice

Author: Cataldo Schietroma, Iman Sahly, Diane Carette, Andrea Lelli, Elise Pepermans, Christine Petit, José-Alain Sahel, Vincent Michel, Jean-Pierre Hardelin, Aziz El-Amraoui, Amrit Estivalet, Amel Bahloul, Asadollah Aghaie, Inga Ebermann, Eric Dufour, Dominique Weil, Isabelle Perfettini, and Maria Iribarne
Subjects: Retinal degeneration, Swine, Usher syndrome, Cadherin Related Proteins, Cell Cycle Proteins, Nerve Tissue Proteins, Myosins, Biology, Cell junction, Retina, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Retinal Dystrophies, Myosin, otorhinolaryngologic diseases, medicine, Animals, Humans, Protein Precursors, Research Articles, 030304 developmental biology, 0303 health sciences, Cadherin, Cell Biology, Anatomy, Cadherins, medicine.disease, Photoreceptor outer segment, eye diseases, Cell biology, Cytoskeletal Proteins, Macaca fascicularis, Intercellular Junctions, medicine.anatomical_structure, Myosin VIIa, Human medicine, sense organs, Anura, Carrier Proteins, Usher Syndromes, 030217 neurology & neurosurgery, Photoreceptor Cells, Vertebrate
Abstract: Mice are a poor model for retinal defects caused by type I Usher syndrome (USH1) because their photoreceptors have almost no calyceal processes, the structures in which all USH1 proteins are detected in other vertebrates., The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins—myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans—do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner–outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients.
Published: 2012
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9. Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids

Author: Sylviane Hoos, Jean-Pierre Hardelin, Christine Petit, Vincent Michel, Patrick England, Anne Houdusse, Amel Bahloul, Sylvie Nouaille, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique des Macromolécules et de leurs Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut Pasteur [Paris] (IP), Collège de France (CdF (institution)), This work was supported by LHW-Stiftung, Fondation Orange, Conny Maeva Foundation, ANR-05-MRAR-015-01, Raymonde and Guy Strittmatter Foundation (under the aegis of Fondation de France), FAUN Stiftung (Suchert Foundation). Funding to pay the Open Access Charge was provided by Unite de Genetique et Physiologie de l'Audition, Institut Pasteur, France., The authors thank Muriel Delepierre for NMR spectra, Raphaël Etournay and Alexandre Chenal for their advice in the preparation of LUV, Beatrice Amigues for myosin VIIa tail preparation, Bruno Baron for circular dichroism experiments, Jacqueline Levilliers for her help in the manuscript preparation and the staff of Dynamic Imaging platform of the Pasteur Institute., ANR-05-MRAR-0015,Usher type I,Physiopathologie du syndrome de Usher de type I : de la structure de la myosine VIIa et de l'harmonine à leur fonction dans les cellules ciliées auditives(2005), ENGLAND, Patrick, and Programme pluriannuel de recherche sur les maladies rares - Physiopathologie du syndrome de Usher de type I : de la structure de la myosine VIIa et de l'harmonine à leur fonction dans les cellules ciliées auditives - - Usher type I2005 - ANR-05-MRAR-0015 - MRAR - VALID
Subjects: Male, MESH: Cytoskeletal Proteins, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Plasma protein binding, MESH: Mice, Knockout, MESH: Cadherins, Mice, MESH: Protein Structure, Tertiary, Myosin, MESH: Hair Cells, Auditory, MESH: Animals, Ternary complex, Phospholipids, Genetics (clinical), Mice, Knockout, MESH: Protein Multimerization, Articles, General Medicine, Cadherins, [SDV] Life Sciences [q-bio], Biochemistry, Myosin VIIa, Female, Usher Syndromes, Protein Binding, Gene isoform, PDZ domain, MESH: Carrier Proteins, macromolecular substances, Myosins, Biology, Cell Line, MESH: Cell Cycle Proteins, Hair Cells, Auditory, otorhinolaryngologic diseases, Genetics, Molecular motor, Animals, Humans, MESH: Myosin VIIa, MESH: Protein Binding, MESH: Usher Syndromes, MESH: Mice, Molecular Biology, MESH: Phospholipids, MESH: Humans, Cadherin, MESH: Myosins, MESH: Male, Protein Structure, Tertiary, MESH: Cell Line, Cytoskeletal Proteins, Disease Models, Animal, Cytoplasm, Biophysics, sense organs, Protein Multimerization, MESH: Disease Models, Animal, Carrier Proteins, MESH: Female
Abstract: International audience; Cadherin-23 is a component of early transient lateral links of the auditory sensory cells' hair bundle, the mechanoreceptive structure to sound. This protein also makes up the upper part of the tip links that control gating of the mechanoelectrical transduction channels. We addressed the issue of the molecular complex that anchors these links to the hair bundle F-actin core. By using surface plasmon resonance assays, we show that the cytoplasmic regions of the two cadherin-23 isoforms that do or do not contain the exon68encoded peptide directly interact with harmonin, a submembrane PDZ (post-synaptic density, disc large, zonula occludens) domain-containing protein, with unusually high affinity. This interaction involves the harmonin Nter-PDZ1 supramodule, but not the C-terminal PDZ-binding motif of cadherin-23. We establish that cadherin-23 directly binds to the tail of myosin VIIa. Moreover, cadherin-23, harmonin and myosin VIIa can form a ternary complex, which suggests that myosin VIIa applies tension forces on hair bundle links. We also show that the cadherin-23 cytoplasmic region, harmonin and myosin VIIa interact with phospholipids on synthetic liposomes. Harmonin and the cytoplasmic region of cadherin-23, both independently and as a binary complex, can bind specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2), which may account for the role of this phospholipid in the adaptation of mechanoelectrical transduction in the hair bundle. The distributions of cadherin-23, harmonin, myosin VIIa and PI(4,5)P 2 in the growing and mature auditory hair bundles as well as the abnormal locations of harmonin and myosin VIIa in cadherin-23 null mutant mice strongly support the functional relevance of these interactions.
Published: 2010
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10. Cochlear outer hair cells undergo an apical circumference remodeling constrained by the hair bundle shape

Author: Christine Petit, Dominique Weil, Michel Leibovici, Vincent Michel, Isabelle Foucher, Nadège Cayet, Raphaël Etournay, Jean-Pierre Hardelin, Jacques Boutet de Monvel, Léa Lepelletier, Etournay, Raphael, Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Université Paris Diderot - Paris 7 (UPD7), Microscopie Ultrastructurale (Plate-forme), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie du Développement, Institut Pasteur [Paris] (IP), Université Paris-Sud - Paris 11 (UP11), Développement, évolution et plasticité du système nerveux (DEPSN), Centre National de la Recherche Scientifique (CNRS), R.E. and L.L. received fellowships from the Collège de France and the Fondation pour la Recherche Médicale, respectively, R.E. acknowledges a Marie Curie fellowship from the EU 7th Framework Programme (FP7), J.B.M. acknowledges support from the Hugot Foundation of the Collège de France.This work was supported by grants from the Fondation Raymonde et Guy Strittmatter, the Réunica-Prévoyance Group, European Commission FP6 Integrated Project EuroHear (LSHG CT-2004-512063), the A. & M. Suchert-Retina Kontra Blindheit Stiftung and the French National Research Agency., Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]
Subjects: MESH: Neurons, MESH: Hair Cells, Auditory, Outer, Cell junction, Mice, 0302 clinical medicine, MESH: Cochlea, Myosin, Scanning, MESH: Animals, MESH: Organ of Corti, Cytoskeleton, Auditory, Organ of Corti, Neurons, Microscopy, 0303 health sciences, Goats, Cilium, Ear, Anatomy, Cochlea, Cell biology, Hair Cells, medicine.anatomical_structure, Mechanosensitive channels, MESH: Microscopy, Electron, Scanning, MESH: Microscopy, Electron, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Outer, Electron, MESH: Goats, 03 medical and health sciences, MESH: Cilia, medicine, Animals, Cilia, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Molecular Biology, 030304 developmental biology, Apical constriction, Inner, Hair Cells, Auditory, Outer, Microscopy, Electron, Ear, Inner, Microscopy, Electron, Scanning, sense organs, MESH: Ear, Inner, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Epithelial cells acquire diverse shapes relating to their different functions. This is particularly relevant for the cochlear outer hair cells (OHCs), whose apical and basolateral shapes accommodate the functioning of these cells as mechano-electrical and electromechanical transducers, respectively. We uncovered a circumferential shape transition of the apical junctional complex (AJC) of OHCs, which occurs during the early postnatal period in the mouse, prior to hearing onset. Geometric analysis of the OHC apical circumference using immunostaining of the AJC protein ZO1 and Fourier-interpolated contour detection characterizes this transition as a switch from a rounded-hexagon to a non-convex circumference delineating two lateral lobes at the neural side of the cell, with a negative curvature in between. This shape tightly correlates with the 'V'-configuration of the OHC hair bundle, the apical mechanosensitive organelle that converts sound-evoked vibrations into variations in cell membrane potential. The OHC apical circumference remodeling failed or was incomplete in all the mouse mutants affected in hair bundle morphogenesis that we tested. During the normal shape transition, myosin VIIa and myosin II (A and B isoforms) displayed polarized redistributions into and out of the developing lobes, respectively, while Shroom2 and F-actin transiently accumulated in the lobes. Defects in these redistributions were observed in the mutants, paralleling their apical circumference abnormalities. Our results point to a pivotal role for actomyosin cytoskeleton tensions in the reshaping of the OHC apical circumference. We propose that this remodeling contributes to optimize the mechanical coupling between the basal and apical poles of mature OHCs.
Published: 2010
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11. Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells

Author: Elisa Caberlotto, Jean-Yves Tinevez, Christine Petit, Christophe Houbron, Guy P. Richardson, Emilie Bizard, Pascal Martin, Vincent Michel, Nicolas Michalski, Alexander F. J. van Aken, Gaelle M. Lefèvre, Jean-Pierre Hardelin, Corné J. Kros, Dominique Weil, Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Génétique des Déficits Sensoriels, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Life Sciences, University of Sussex, Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Imagopole (CITECH), Institut Pasteur [Paris], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), N.M. was supported by a fellowship from the Fondation pour la Recherche Médicale and the Ministère de l'Education Nationale, de la Recherche et de la Technologie. This work was supported by the Fondation Raymonde et Guy Strittmatter, the European Commission FP6 Integrated Project EuroHear LSHG-CT-2004-512063, Ernst-Jung Stiftung für Medizin Preis, FAUN Stiftung (Suchert Foundation) and the Ministère de la Recherche-ACI Interface Physique-Chimie-Biologie-DRAB02/102., We thank Jacqueline Levilliers for her help in the preparation of the manuscript and Jacques Boutet de Monvel for critical reading of the manuscript., Collège de France - Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Tinevez, Jean-Yves
Subjects: Scaffold protein, Patch-Clamp Techniques, MESH: Cytoskeletal Proteins, MESH: Mice, Mutant Strains, Physiology, [SDV]Life Sciences [q-bio], Stereocilia (inner ear), Clinical Biochemistry, MESH: Adaptation, Physiological, Action Potentials, Fluorescent Antibody Technique, Cell Cycle Proteins, MESH: Mechanotransduction, Cellular / physiology, Mechanotransduction, Cellular, Mice, MESH: Hair Cells, Auditory, Inner / metabolism, 0302 clinical medicine, MESH: Animals, MESH: Fluorescent Antibody Technique, Mechanoelectrical transduction, 0303 health sciences, Anatomy, Hair bundle, Adaptation, Physiological, Cochlea, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, MESH: Carrier Proteins / metabolism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hair cell, Transduction (physiology), Vestibule, Vestibular system, MESH: Microscopy, Electron, Scanning, PDZ domain, Biology, 03 medical and health sciences, MESH: Action Potentials / physiology, Physiology (medical), MESH: Patch-Clamp Techniques, otorhinolaryngologic diseases, medicine, Animals, Inner ear, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adaptation, MESH: Mice, Harmonin, 030304 developmental biology, Hair Cells, Auditory, Inner, Mice, Mutant Strains, Cytoskeletal Proteins, Microscopy, Electron, Scanning, Biophysics, sense organs, Carrier Proteins, Tip link, 030217 neurology & neurosurgery, Neuroscience
Abstract: We assessed the involvement of harmonin-b, a submembranous protein containing PDZ domains, in the mechanoelectrical transduction machinery of inner ear hair cells. Harmonin-b is located in the region of the upper insertion point of the tip link that joins adjacent stereocilia from different rows and that is believed to gate transducer channel(s) located in the region of the tip link's lower insertion point. In Ush1cdfcr-2J/dfcr-2J mutant mice defective for harmonin-b, step deflections of the hair bundle evoked transduction currents with altered speed and extent of adaptation. In utricular hair cells, hair bundle morphology and maximal transduction currents were similar to those observed in wild-type mice, but adaptation was faster and more complete. Cochlear outer hair cells displayed reduced maximal transduction currents, which may be the consequence of moderate structural anomalies of their hair bundles. Their adaptation was slower and displayed a variable extent. The latter was positively correlated with the magnitude of the maximal transduction current, but the cells that showed the largest currents could be either hyperadaptive or hypoadaptive. To interpret our observations, we used a theoretical description of mechanoelectrical transduction based on the gating spring theory and a motor model of adaptation. Simulations could account for the characteristics of transduction currents in wild-type and mutant hair cells, both vestibular and cochlear. They led us to conclude that harmonin-b operates as an intracellular link that limits adaptation and engages adaptation motors, a dual role consistent with the scaffolding property of the protein and its binding to both actin filaments and the tip link component cadherin-23. Electronic supplementary material The online version of this article (doi:10.1007/s00424-009-0711-x) contains supplementary material, which is available to authorized users.
Published: 2009
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12. Stereocilin-deficient mice reveal the origin of cochlear waveform distortions

Author: Elisabeth Verpy, Jean-Pierre Hardelin, Gaelle M. Lefèvre, Christine Petit, Ghislaine Hamard, Paul Avan, Michel Leibovici, Dominique Weil, Richard J. Goodyear, Guy P. Richardson, and Carine Houdon
Subjects: Male, Hearing loss, Acoustics, Otoacoustic emission, Stimulus (physiology), Sensory receptor, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Hair Cells, Auditory, otorhinolaryngologic diseases, medicine, Animals, Waveform, Inner ear, Cochlea, 030304 developmental biology, Mice, Knockout, Physics, 0303 health sciences, Multidisciplinary, Proteins, Immunohistochemistry, medicine.anatomical_structure, Acoustic Stimulation, Gene Expression Regulation, Intercellular Signaling Peptides and Proteins, Female, sense organs, Hair cell, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions1. These distortions reflect non-linear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility2. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus3. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. As both cochlear amplification and distortion originate from the outer hair cells, one of the two types of sensory receptor cells, it has been speculated that they stem from a common mechanism. Here, the non-linearity underlying cochlear waveform distortions is shown to rely on the presence of stereocilin, a protein defective in a recessive form of human deafness4. Stereocilin was detected in association with horizontal top connectors5-7, lateral links that join adjacent stereocilia within the outer hair cell’s hair bundle, and these links were absent in stereocilin-null mutant mice. These mice become progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic non-linear behaviour of the mechanoelectrical transducer channel.
Published: 2008
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13. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity

Author: Carine Monnier, Luis Augusto Teixeira, Jean-Philippe Pin, Gilles Labesse, Ludovic Fabre, Catherine Dodé, Jean-Pierre Hardelin, and Philippe Rondard
Subjects: Models, Molecular, medicine.medical_specialty, Receptors, Peptide, Kallmann syndrome, Mutant, Mutation, Missense, Dominant-Negative Mutation, Biology, medicine.disease_cause, Cell Line, Receptors, G-Protein-Coupled, Gastrointestinal Hormones, Mice, Internal medicine, Genetics, medicine, Animals, Humans, Amino Acid Sequence, Receptor, Molecular Biology, Genetics (clinical), G protein-coupled receptor, Mutation, Neuropeptides, Prokineticin receptor 2, Kallmann Syndrome, Articles, General Medicine, medicine.disease, Molecular biology, Protein Structure, Tertiary, Endocrinology, Calcium, Signal transduction, Signal Transduction
Abstract: Kallmann syndrome (KS) combines hypogonadism due to gonadotropin-releasing hormone deficiency, and anosmia or hyposmia, related to defective olfactory bulb morphogenesis. In a large series of KS patients, ten different missense mutations (p.R85C, p.R85H, p.R164Q, p.L173R, p.W178S, p.Q210R, p.R268C, p.P290S, p.M323I, p.V331M) have been identified in the gene encoding the G protein-coupled receptor prokineticin receptor-2 (PROKR2), most often in the heterozygous state. Many of these mutations were, however, also found in clinically unaffected individuals, thus raising the question of their actual implication in the KS phenotype. We reproduced each of the ten mutations in a recombinant murine Prokr2, and tested their effects on the signalling activity in transfected HEK-293 cells, by measuring intracellular calcium release upon ligand-activation of the receptor. We found that all mutated receptors except one (M323I) had decreased signalling activities. These could be explained by different defective mechanisms. Three mutations (L173R, W178S, P290S) impaired cell surface-targeting of the receptor. One mutation (Q210R) abolished ligand-binding. Finally, five mutations (R85C, R85H, R164Q, R268C, V331M) presumably impaired G protein-coupling of the receptor. In addition, when wild-type and mutant receptors were coexpressed in HEK-293 cells, none of the mutant receptors that were retained within the cells did affect cell surface-targeting of the wild-type receptor, and none of the mutant receptors properly addressed at the plasma membrane did affect wild-type receptor signalling activity. This argues against a dominant negative effect of the mutations in vivo.
Published: 2008
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14. A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth

Author: Léa Lepelletier, Dominique Weil, Vincent Michel, Christine Petit, Jean-Pierre Hardelin, Gaelle M. Lefèvre, Uwe Wolfrum, and Emilie Bizard
Subjects: Stereocilia (inner ear), Cadherin Related Proteins, Protocadherin, Cell Cycle Proteins, Nerve Tissue Proteins, Myosins, Biology, Mechanotransduction, Cellular, Mice, CDH23, Pregnancy, otorhinolaryngologic diseases, medicine, Animals, Humans, Inner ear, Protein Precursors, Molecular Biology, Actin, Mice, Knockout, Cadherin, Dyneins, Anatomy, Cadherins, Mice, Mutant Strains, Cochlea, Cell biology, Cytoskeletal Proteins, Disease Models, Animal, Phenotype, medicine.anatomical_structure, Myosin VIIa, Microscopy, Electron, Scanning, Female, sense organs, Carrier Proteins, Usher Syndromes, Tip link, PCDH15, Developmental Biology
Abstract: The planar polarity and staircase-like pattern of the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin 23,protocadherin 15 or sans cause Usher syndrome type I (USH1, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans and hair bundle disorganization in mice. Whether the USH1 proteins are involved in common hair bundle morphogenetic processes is unknown. Here, we show that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-52° mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17. Abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin 23 and protocadherin 15, all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth,harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin 23 and protocadherin 15. This positional change did not occur in mice deficient for cadherin 23 or protocadherin 15. We suggest that tension forces applied to the early lateral links and to the tip link, both of which can be anchored to actin filaments via harmonin-b, play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter.
Published: 2008
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15. Molecular Characterization of the Ankle-Link Complex in Cochlear Hair Cells and Its Role in the Hair Bundle Functioning

Author: Pascal Martin, Nicolas Michalski, Dominique Weil, Amel Bahloul, Gaelle M. Lefèvre, Hideshi Yagi, Jean-Pierre Hardelin, Jérémie Barral, Vincent Michel, Makoto Sato, Sébastien Chardenoux, Christine Petit, Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), and Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell type, Patch-Clamp Techniques, Stereocilia (inner ear), PDZ domain, Biology, Mechanotransduction, Cellular, Membrane Potentials, Receptors, G-Protein-Coupled, Adenylyl cyclase, Mice, chemistry.chemical_compound, Organ Culture Techniques, Hair Cells, Auditory, adenylyl cyclase 6, otorhinolaryngologic diseases, Animals, Cilia, Egtazic Acid, Cochlea, Chelating Agents, Mice, Knockout, Extracellular Matrix Proteins, Cadherin, General Neuroscience, hair bundle, Subtilisin, ankle link, Gene Expression Regulation, Developmental, Membrane Proteins, Articles, Anatomy, Embryo, Mammalian, Transmembrane protein, Cell biology, Animals, Newborn, chemistry, Microscopy, Electron, Scanning, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sense organs, Vlgr1, Carrier Proteins, Usher syndrome, Transduction (physiology), Adenylyl Cyclases
Abstract: International audience; Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. Here, we show that the transmembrane protein usherin, the putative transmembrane protein vezatin, and the PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-containing submembrane protein whirlin are colocalized with Vlgr1 at the stereocilia base in developing cochlear hair cells and are absent in Vlgr1 Ϫ/Ϫ mice that lack the ankle links. Direct in vitro interactions between these four proteins further support their involvement in a molecular complex associated with the ankle links and scaffolded by whirlin. In addition, the delocalization of these proteins in myosin VIIa defective mutant mice as well as the myosin VIIa tail direct interactions with vezatin, whirlin, and, we show, Vlgr1 and usherin, suggest that myosin VIIa conveys proteins of the ankle-link complex to the stereocilia. Adenylyl cyclase 6, which was found at the base of stereocilia, was both overexpressed and mislocated in Vlgr1 Ϫ/Ϫ mice. In postnatal day 7 Vlgr1 Ϫ/Ϫ mice, mechanoelectrical transduction currents evoked by displacements of the hair bundle toward the tallest stereocilia (i.e., in the excitatory direction) were reduced in outer but not inner hair cells. In both cell types, stimulation of the hair bundle in the opposite direction paradoxically resulted in significant transduction currents. The absence of ankle-linkmediated cohesive forces within hair bundles lacking Vlgr1 may account for the electrophysiological results. However, because some long cadherin-23 isoforms could no longer be detected in Vlgr1 Ϫ/Ϫ mice shortly after birth, the loss of some apical links could be involved too. The premature disappearance of these cadherin isoforms in the Vlgr1 Ϫ/Ϫ mutant argues in favor of a signaling function of the ankle links in hair bundle differentiation.
Published: 2007
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16. Connexin30 deficiency causes instrastrial fluid–blood barrier disruption within the cochlear stria vascularis

Author: Dorothée Caille, Jean-Pierre Hardelin, Paolo Meda, Béatrice Regnault, K. Demuth, Christine Petit, Nathalie Janel, Nadège Cayet, Martine Cohen-Salmon, Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Puces à ADN (Plate-Forme 2) (PF2), Institut Pasteur [Paris] (IP), Microscopie électronique, Université de Genève = University of Geneva (UNIGE), 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), Modèles de dérégulation génique : trisomie 21 et hyperhomocystéinémie (EA_3508), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Collège de France (CdF (institution))
Subjects: Endothelium, Endocochlear potential, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Betaine—homocysteine S-methyltransferase, Fluorescent Antibody Technique, Biology, Connexins, Mice, Basal (phylogenetics), Microscopy, Electron, Transmission, Connexin 30, medicine, Animals, Freeze Fracturing, Cysteine, Endothelial dysfunction, Hearing Loss, Chromatography, High Pressure Liquid, Cochlea, DNA Primers, Mice, Knockout, Multidisciplinary, Gene Expression Profiling, Stria Vascularis, Biological Sciences, Microarray Analysis, medicine.disease, Epithelium, Cell biology, medicine.anatomical_structure, Betaine-Homocysteine S-Methyltransferase, Biochemistry, Cochlear Microphonic Potentials, Endothelium, Vascular, Cochlear microphonic potential
Abstract: The endocochlear potential (EP) is essential to hearing, because it provides approximately half of the driving force for the mechanoelectrical transduction current in auditory hair cells. The EP is produced by the stria vascularis (SV), a vascularized bilayer epithelium of the cochlea lateral wall. The absence of the gap junction protein connexin30 (Cx30) in Cx30 −/− mice results in the SV failure to produce an EP, which mainly accounts for the severe congenital hearing impairment of these mice. Here, we show that the SV components of the EP electrogenic machinery and the epithelial barriers limiting the intrastrial fluid space, which are both necessary for the EP production, were preserved in Cx30 −/− mice. In contrast, the endothelial barrier of the capillaries supplying the SV was disrupted before EP onset. This disruption is expected to result in an intrastrial electric shunt that is sufficient to account for the absence of the EP production. Immunofluorescence analysis of wild-type mice detected Cx30 in the basal and intermediate cells of the SV but not in the endothelial cells of the SV capillaries. Moreover, dye-coupling experiments showed that endothelial cells were not coupled to the SV basal, intermediate, and marginal cells. SV transcriptome analysis revealed a significant down-regulation of betaine homocysteine S -methyltransferase ( Bhmt ) in the Cx30 −/− mice, which was restricted to the SV and resulted in a local increase in homocysteine, a known factor of endothelial dysfunction. Disruption of the SV endothelial barrier is a previously undescribed pathogenic process underlying hearing impairment.
Published: 2007
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17. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

Author: Sylvie Dartevelle, Asadollah Aghaie, Maryline Beurg, E. Sylvester Vizi, Sedigheh Delmaghani, Isabelle Perfettini, Jean Pierre Hardelin, Nicolas Thelen, Alice Emptoz, Guillaume Soubigou, Máté Aller, Didier Dulon, Michel Leibovici, Marc Thiry, Christine Petit, Fabrice Giraudet, Anaïs Meyer, Paul Avan, Tibor Zelles, Saaid Safieddine, Jean Defourny, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Syndrome de Usher et autres atteintes rétino-cochléaires, Institut de la Vision, 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)-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), 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), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Unit of Cell and Tissue Biology, GIGA-Neurosciences, Université de Liège-CHU Sart Tilman, Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA), Department of Pharmacology and Pharmacotherapy, Semmelweis University [Budapest], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), This work was supported by the Louis-Jeantet Foundation, ANR-NKTH 'HearDeafTrheareat' (2010-INTB-1402-23 01 and TÉT_10-1-2011- 0421), Fondation Bettencourt Schueller, Fondation Agir pour l’Audition, Humanis Novalis- Taitbout, Réunica-Prévoyance, BNP Paribas, and the French state program ‘‘Investissements d’Avenir’’ (ANR-10-LABX-65) (to C.P.)., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-INTB-0002,HearDeafTreat,Audition et surdité: Mécanismes moléculaires et approches thérapeutiques(2010), Petit, Christine, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Audition et surdité: Mécanismes moléculaires et approches thérapeutiques - - HearDeafTreat2010 - ANR-10-INTB-0002 - Blanc international 2010 - VALID, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported by the Louis-Jeantet Foundation, Fondation BettencourtSchueller, Fondation Agir pour l’Audition, Humanis Novalis-Taitbout, Reunica-Pre´ voyance, BNP Paribas, Chaire Génétique et physiologie cellulaire, CHU Sart Tilman-Université de Liège, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]
Subjects: Auditory Pathways, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peroxisome Proliferation, Stimulation, Nerve Tissue Proteins, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sound exposure, Mice, 0302 clinical medicine, Transcription (biology), Hair Cells, Auditory, medicine, Peroxisomes, otorhinolaryngologic diseases, Auditory system, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), fungi, Proteins, food and beverages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, Peroxisome, Phenotype, Cell biology, Oxidative Stress, medicine.anatomical_structure, Hearing Loss, Noise-Induced, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.
Published: 2015
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18. Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly

Author: Vincent Michel, Nicolas Michalski, Isabelle Perfettini, Pierre Legrain, Jean-Pierre Hardelin, Yasuhiro Yamasaki, Guy P. Richardson, Aziz El-Amraoui, Benjamin Delprat, Richard J. Goodyear, Christine Petit, Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Sussex, RIKEN Center for Brain Science [Wako] (RIKEN CBS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hybrigenics [Paris], Hybrigenics, and This work was supported by Fondation pour la Recherche Médicale (ARS2000), European Community (QLG2-CT-1999-00988). B.D. has a fellowship from Letten F. Saugstad's Fund. R.G. and G.R. are supported by The Wellcome Trust (grant 071394/Z/03/Z).
Subjects: Gene isoform, [SDV]Life Sciences [q-bio], PDZ domain, Nerve Tissue Proteins, Myosins, Biology, Cell Line, Gene product, Mice, Dogs, Chlorocebus aethiops, Hair Cells, Auditory, Myosin, otorhinolaryngologic diseases, Genetics, Molecular motor, Animals, Humans, Cilia, Molecular Biology, Genetics (clinical), Stereocilium, Stereocilia, Membrane Proteins, General Medicine, Actins, Transmembrane protein, Protein Structure, Tertiary, Rats, Cell biology, sense organs, Protein Binding
Abstract: International audience; Defects in myosin XVa and the PDZ domain-containing protein, whirlin, underlie deafness in humans and mice. Hair bundles of mutant mice defective for either protein have abnormally short stereocilia. Here, we show that whirlin, like myosin XVa, is present at the very tip of each stereocilium in the developing and mature hair bundles of the cochlear and vestibular system. We found that myosin XVa SH3-MyTH4 region binds to the short isoform of whirlin (PR-PDZ3) that can rescue the stereocilia growth defect in whirlin defective mice. Moreover, the C-terminal MyTH4-FERM region of myosin XVa binds to the PDZ1 and PDZ2 domains of the long whirlin isoform. We conclude that a direct myosin XVa-whirlin interaction at the stereocilia tip is likely to control the elongation of stereocilia. Whirlin, unlike myosin XVa, is also transiently localized in the basal region of developing stereocilia in rat vestibular and cochlear hair cells until P4 and P12, respectively. Notably, whirlin also interacts with myosin VIIa that is present along the entire length of the stereocilia. Finally, we show that the transmembrane netrin-G1 ligand (NGL-1) binds to the PDZ1 and PDZ2 domains of whirlin and has an extracellular region that homophilically self-interacts in a Ca 21-dependent manner. The interaction between whirlin and NGL-1 might be involved in the stabilization of interstereociliar links.
Published: 2004
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19. The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells

Author: Richard J. Goodyear, Typhaine Dupont, Mohamed Makrelouf, Paul Avan, Jean-Pierre Hardelin, Muriel Holder, Elise Pepermans, Amel Bahloul, Souad Gherbi, Samia Abdi, Vincent Michel, Christine Petit, Sandrine Marlin, Guy P. Richardson, Akila Zenati, Crystel Bonnet, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), School of Life Sciences, University of Sussex, Syndrome de Usher et autres atteintes rétino-cochléaires, Institut de la Vision, 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)-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), Génétique et Biologie, Université Saâd Dahlab Blida 1 (UB1)- Centre Hospitalo-Universitaire de Blida (CHU Blida), Centre de référence des Surdités Génétiques [CHU Necker, Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Biochimie Génétique, CHU de Bab El Oued-Université d'Alger 1, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Equipe Biophysique Neurosensorielle [Neuro-Dol], Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), EP wassupported by a fellowship from the Fondation Raymonde et Guy Strittmatter.This work was supported by ERC-Hair bundle (ERC-2011-ADG_294570), FoundationBNP Paribas and LHW-Stiftung to CP, Tassili project funding to CP andAZ and Wellcome Trust programme grant (WT087377) to GR. This workperformed in the frame of the LABEX LIFESENSES [reference ANR-10-LABX-65]was supported by French state funds managed by the ANR within the Investissementsd’Avenir programme under reference ANR-11-IDEX-0004-02., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), Chaire Génétique et physiologie cellulaire, Université de Saâd Dahlab [Blida] (USDB )- Centre Hospitalo-Universitaire de Blida (CHU Blida), Centre de référence des Surdités Génétiques, Petit, Christine, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, and Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID
Subjects: Gene isoform, Male, protocadherin-15, tip-link, Protocadherin, Cadherin Related Proteins, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Gene Therapy & Genetic Disease, Mechanotransduction, Cellular, Frameshift mutation, Mice, Report, deafness, Conditional gene knockout, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, Humans, Protein Isoforms, Inner ear, Protein Precursors, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Frameshift Mutation, stereocilia, Genetics, Mice, Knockout, tip-link Subject Categories Genetics, auditory mechano-electrical transduction, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Cadherins, Cell biology, medicine.anatomical_structure, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Mutation, Molecular Medicine, Female, Hair cell, Human medicine, Tip link, PCDH15, Neuroscience
Abstract: International audience; Protocadherin-15 (Pcdh15) is a component of the tip-links, the extracellular filaments that gate hair cell mechano-electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cyto-plasmic domains; they are thought to function redundantly in mechano-electrical transduction during hair-bundle development, but whether any of these isoforms composes the tip-link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15 ex38-fl/ex38-fl Myo15-cre +/À) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15-CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano-electrical trans-duction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.
Published: 2014
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20. EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness

Author: Hayet Lebdi, Christine Petit, Malek Louha, Yahia Rous, Andrea Lelli, Asma Behlouli, Samia Abdi, Ahmed Cheknane, Mohamed Makrelouf, Crystel Bonnet, Cataldo Schietroma, Jean-Pierre Hardelin, Akila Zenati, Aicha Bouaita, Kamel Boudjelida, Laboratoire de Biochimie Génétique, CHU de Bab El Oued-Université d'Alger 1, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Génétique et Biologie, Université Saâd Dahlab Blida 1 (UB1)- Centre Hospitalo-Universitaire de Blida (CHU Blida), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service ORL, Centre Hospitalo-Universitaire de Blida (CHU Blida), Service Ophtalmologie, This work was supported by grants from the LHW-Stiftung, ERC grant 'Hair bundle' (ERC-2011-AdG 294570), Foundation BNP Paribas, 'Lifesenses' Labex, the Tassili Project and the Algerian government., Chaire Génétique et physiologie cellulaire, Université de Saâd Dahlab [Blida] (USDB )- Centre Hospitalo-Universitaire de Blida (CHU Blida), and BMC, Ed.
Subjects: Male, Hearing loss, Stereocilia (inner ear), Hearing Loss, Sensorineural, Nonsense mutation, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, EPS8, Stereocilia, 03 medical and health sciences, Mice, 0302 clinical medicine, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Epidermal growth factor receptor pathway substrate 8, Animals, Humans, Genetics(clinical), Pharmacology (medical), Exome, Actin-binding protein, Genetics (clinical), Exome sequencing, 030304 developmental biology, Adaptor Proteins, Signal Transducing, DNA Primers, Medicine(all), Genetics, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Congenital deafness, Research, General Medicine, Actins, 3. Good health, Pedigree, Whole-exome sequencing, biology.protein, Female, medicine.symptom, Actin dynamics, Stereocilia bundle, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Almost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness. METHOD: Whole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved. RESULTS: A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8-/- mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia. CONCLUSION: This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.
Published: 2014
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21. Unconventional Myosin VIIA Is a Novel A-kinase-anchoring Protein

Author: Jean-Pierre Hardelin, Aziz El-Amraoui, Christine Petit, Sylvie Nouaille, Polonca Küssel-Andermann, Jacques Camonis, Saaid Safieddine, Génétique des Déficits sensoriels, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Génétique et expression des oncogènes, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: A-kinase-anchoring protein, Myosin light-chain kinase, [SDV]Life Sciences [q-bio], Moesin, Protein subunit, macromolecular substances, Myosins, Biology, Biochemistry, Substrate Specificity, Mice, Ezrin, Radixin, Myosin, Escherichia coli, otorhinolaryngologic diseases, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Protein kinase A, Molecular Biology, Binding Sites, Dyneins, Cell Biology, Cyclic AMP-Dependent Protein Kinases, eye diseases, Cell biology, Myosin VIIa, sense organs, Protein Binding
Abstract: To gain an insight into the cellular function of the unconventional myosin VIIA, we sought proteins interacting with its tail region, using the yeast two-hybrid system. Here we report on one of the five candidate interactors we identified, namely the type I alpha regulatory subunit (RI alpha) of protein kinase A. The interaction of RI alpha with myosin VIIA tail was demonstrated by coimmunoprecipitation from transfected HEK293 cells. Analysis of deleted constructs in the yeast two-hybrid system showed that the interaction of myosin VIIA with RI alpha involves the dimerization domain of RI alpha. In vitro binding assays identified the C-terminal "4.1, ezrin, radixin, moesin" (FERM)-like domain of myosin VIIA as the interacting domain. In humans and mice, mutations in the myosin VIIA gene underlie hereditary hearing loss, which may or may not be associated with visual deficiency. Immunohistofluorescence revealed that myosin VIIA and RI alpha are coexpressed in the outer hair cells of the cochlea and rod photoreceptor cells of the retina. Our results strongly suggest that myosin VIIA is a novel protein kinase A-anchoring protein that targets protein kinase A to definite subcellular sites of these sensory cells.
Published: 2000
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22. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness

Author: Jean-Pierre Hardelin, Jacques Young, Sandrine Marlin, Christine Francannet, Chrystel Leroy, Jérôme Bertherat, Virginie Bodereau, O. Verier-Mine, Delphine Dupin-Deguine, F. Archambeaud, Viviane Baral, Séverine Marcos, François-Joseph Kurtz, Michel Goossens, Catherine Dodé, Asma Chaoui, Veronique Pingault, Yuli Watanabe, Corinne Fouveaut, Nadege Bondurand, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biochimie et Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'endocrinologie, Centre Hospitalier de Valenciennes, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Service de pédiatrie, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville)-Hôpital Bel Air, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'Endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence pour les Maladies Rares, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Institut de la Santé et de la Recherche Médicale (Inserm) and the Agence Nationale de la Recherche (ANR-JCJC-2010 to NB and ANR-2009-GENOPAT-017 to CD). AC is a recipient of a fellowship from the Fondation pour la Recherche Médicale (FRM). SM is receiving a salary on theANR-2009-GENOPAT-017 grant., Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], CHU - HÔTEL-DIEU Clermont-Ferrand, Hôpital Bel Air-Centre hospitalier régional Metz-Thionville ( CHR Metz-Thionville ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Centre de Référence pour les Maladies Rares, Génétique et physiologie de l'audition, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Bel Air-Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Guellaen, Georges
Subjects: Olfactory system, Male, medicine.medical_specialty, Indoles, Kallmann syndrome, SOX10, DNA Mutational Analysis, Anosmia, Biology, Deafness, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Olfactory nerve, Hypogonadotropic hypogonadism, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Animals, Humans, Genetics(clinical), Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Waardenburg syndrome, SOXE Transcription Factors, Galactosides, Kallmann Syndrome, Olfactory Pathways, medicine.disease, Endocrinology, Mutation, embryonic structures, Female, Olfactory ensheathing glia, France, medicine.symptom, Neuroglia, 030217 neurology & neurosurgery, HeLa Cells, Plasmids
Abstract: International audience; Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.
Published: 2013
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23. Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

Author: Dominique Weil, Sébastien Chardenoux, Paul Avan, Vincent Michel, Nicolas Michalski, Olinda Alegria-Prévot, Marcio Do Cruzeiro, Isabelle Perfettini, Guy P. Richardson, Richard J. Goodyear, Isabelle Foucher, Elisa Caberlotto, Jean-Pierre Hardelin, Amel Bahloul, Christine Petit, Elise Pepermans, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Life Sciences, University of Sussex, Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), This work was supported by FAUN Stiftung (Suchert Foundation), Fondation Raymonde and Guy Strittmatter,LHW-Stiftung, the Conny Maeva Charitable Foundation, Fondation Orange, and the Louis-Jeantet Foundation. R.J.G. and G.P.R. are supported by The Wellcome Trust, Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), michalski, nicolas, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] ( PRHTEC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Neuro-Dol ( Neuro-Dol ), Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), and Collège de France ( CdF )
Subjects: Scaffold protein, MESH: Signal Transduction, MESH: Protein Precursors, MESH : Immunohistochemistry, [SDV]Life Sciences [q-bio], MESH : Actins, Fluorescent Antibody Technique, MESH : Analysis of Variance, MESH: Mice, Knockout, MESH: Cadherins, Polymerization, Mice, 0302 clinical medicine, MESH: Genetic Vectors, MESH: Hair Cells, Auditory, MESH : Polymerization, MESH: Animals, MESH: Nerve Tissue Proteins, Mechanotransduction, MESH : Protein Precursors, MESH : Nerve Tissue Proteins, MESH: Fluorescent Antibody Technique, Mice, Knockout, 0303 health sciences, Multidisciplinary, MESH: Electrophysiology, Cilium, Biological Sciences, Cadherins, Immunohistochemistry, MESH : Genetic Vectors, Cell biology, [SDV] Life Sciences [q-bio], Electrophysiology, medicine.anatomical_structure, MESH: Polymerization, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Cadherins, Transduction (physiology), Engineering sciences. Technology, Signal Transduction, MESH : Microscopy, Electron, Scanning, MESH: Microscopy, Electron, Scanning, Genetic Vectors, Cadherin Related Proteins, Nerve Tissue Proteins, Biology, MESH: Actins, MESH : Cilia, 03 medical and health sciences, MESH : Electrophysiology, MESH: Cilia, MESH: Analysis of Variance, MESH : Mice, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cilia, Protein Precursors, MESH : Hair Cells, Auditory, MESH: Mice, Actin, 030304 developmental biology, MESH : Signal Transduction, Analysis of Variance, [ SDV ] Life Sciences [q-bio], Stereocilia, MESH: Immunohistochemistry, Actins, MESH : Fluorescent Antibody Technique, Cytoplasm, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microscopy, Electron, Scanning, MESH : Mice, Knockout, MESH : Animals, sense organs, Tip link, 030217 neurology & neurosurgery
Abstract: The mechanotransducer channels of auditory hair cells are gated by tip-links, oblique filaments that interconnect the stereocilia of the hair bundle. Tip-links stretch from the tips of stereocilia in the short and middle rows to the sides of neighboring, taller stereocilia. They are made of cadherin-23 and protocadherin-15, products of the Usher syndrome type 1 genes USH1D and USH1F, respectively. In this study we address the role of sans, a putative scaffold protein and product of the USH1G gene. In Ush1g −/− mice, the cohesion of stereocilia is disrupted, and both the amplitude and the sensitivity of the transduction currents are reduced. In Ush1g fl/fl Myo15-cre +/− mice, the loss of sans occurs postnatally and the stereocilia remain cohesive. In these mice, there is a decrease in the amplitude of the total transducer current with no loss in sensitivity, and the tips of the stereocilia in the short and middle rows lose their prolate shape, features that can be attributed to the loss of tip-links. Furthermore, stereocilia from these rows undergo a dramatic reduction in length, suggesting that the mechanotransduction machinery has a positive effect on F-actin polymerization. Sans interacts with the cytoplasmic domains of cadherin-23 and protocadherin-15 in vitro and is absent from the hair bundle in mice defective for either of the two cadherins. Because sans localizes mainly to the tips of short- and middle-row stereocilia in vivo, we conclude that it belongs to a molecular complex at the lower end of the tip-link and plays a critical role in the maintenance of this link.
Published: 2011
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24. Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

Author: Dominique Weil, Paolo Gasparini, Isabelle Perfettini, Jean-Pierre Hardelin, Christine Petit, Vincent Michel, Paul Avan, Amel Bahloul, Sylvie Nouaille, Michel Leibovici, Danilo Licastro, Jian Zuo, Cristina Zadro, Isabelle Roux, Marie-Christine Simmler, Bahloul, A, Simmler, Mc, Michel, V, Leibovici, M, Perfettini, I, Roux, I, Weil, D, Nouaille, S, Zuo, J, Zadro, C, Licastro, D, Gasparini, Paolo, Avan, P, Hardelin, Jp, Petit, C., Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Département de neurobiologie du développement, recherche de l'Hôpital St. Jude Children's, St Jude Children's Research Hospital, Unité de génétique médicale, Département des sciences de la reproduction et le développement, IRCCS de l'Université de Trieste, Università degli studi di Trieste = University of Trieste, Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Région Ile-de-France du projet, Grant Numéro: Sésame 2002-E1666 Pasteur-Weizmann Programme commun de recherche (2006-2007), ANR-05-MRAR-0015,Usher type I,Physiopathologie du syndrome de Usher de type I : de la structure de la myosine VIIa et de l'harmonine à leur fonction dans les cellules ciliées auditives(2005), European Project, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Physiologie de l'Audition, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Collège de France (CdF)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Trieste, Università degli studi di Napoli Federico II-RISSC-Lab, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol - Clermont Auvergne (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Collège de France (CDF), Collège de France (CdF), Agence française de recherche national (ANR-Maladies Rares), Nombre de subventions: ANR-05-MRAR-015-01 - Agence française de recherche national (ANR-Maladies Neurologiques et Psychiatriques),Agence française de recherche national (ANR-Maladies Rares), Nombre de subventions: ANR-05-MRAR-015-01 - Agence française de recherche national (ANR-Maladies Neurologiques et Psychiatriques), and Chaire Génétique et physiologie cellulaire
Subjects: mouse model, Deafness, Biology, Polymorphism, Single Nucleotide, adherens junction, Adherens junction, Mice, 03 medical and health sciences, 0302 clinical medicine, Stress, Physiological, Radixin, medicine, otorhinolaryngologic diseases, Animals, Inner ear, Research Articles, Cochlea, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, medicine.disease, Cell biology, noise-induced hearing loss, Intercellular Junctions, medicine.anatomical_structure, Hearing Loss, Noise-Induced, Membrane protein, Organ of Corti, vezatin, Molecular Medicine, Hair cell, organ of Corti, Noise, Gene Deletion, 030217 neurology & neurosurgery, Noise-induced hearing loss
Abstract: International audience; Loud sound exposure is a significant cause of hearing loss worldwide. We asked whether a lack of vezatin, an ubiquitous adherens junction protein, could result in noise-induced hearing loss. Conditional mutant mice bearing non-functional vezatin alleles only in the sensory cells of the inner ear (hair cells) indeed exhibited irreversible hearing loss after only one minute exposure to a 105 dB broadband sound. In addition, mutant mice spontaneously underwent late onset progressive hearing loss and vestibular dysfunction related to substantial hair cell death. We establish that vezatin is an integral membrane protein with two adjacent transmembrane domains, and cytoplasmic N- and C-terminal regions. Late recruitment of vezatin at junctions between MDCKII cells indicates that the protein does not play a role in the formation of junctions, but rather participates in their stability. Moreover, we show that vezatin directly interacts with radixin in its actin-binding conformation. Accordingly, we provide evidence that vezatin associates with actin filaments at cell-cell junctions. Our results emphasize the overlooked role of the junctions between hair cells and their supporting cells in the auditory epithelium resilience to sound trauma.
Published: 2009
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25. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

Author: Chrystel Leroy, Jean-Pierre Hardelin, James Lespinasse, Sébastien Jacquemont, Hélène Du Boullay, Catherine Dodé, Marc Delpech, Sandrine Leclercq, Jean-Michel Dupont, and Corinne Fouveaut
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Kallmann syndrome, DNA Mutational Analysis, Biology, medicine.disease_cause, Compound heterozygosity, Frameshift mutation, Gastrointestinal Hormones, Mice, Gene interaction, Hypogonadotropic hypogonadism, Internal medicine, Genetics, medicine, Missense mutation, Animals, Humans, Genetics (clinical), Alleles, Mutation, Fibroblast growth factor receptor 1, Neuropeptides, Kallmann Syndrome, medicine.disease, Pedigree, Endocrinology, Female
Abstract: Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.
Published: 2008

26. PHR1, an integral membrane protein of the inner ear sensory cells, directly interacts with myosin 1c and myosin VIIa

Author: Nicolas Michalski, Guillaume Pézeron, Laurent Daviet, Aziz El-Amraoui, Pierre Legrain, Stéphane Blanchard, Jean-Pierre Hardelin, Amel Bahloul, Isabelle Roux, Christine Petit, Raphaël Etournay, Génétique des Déficits Sensoriels, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hybrigenics [Paris], Hybrigenics, Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by grants from the EC (QLG2-CT-1999-00988), R & G Strittmatter Foundation, A & M Suchert Kontra Blindheit., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Collège de France - Chaire Génétique et physiologie cellulaire, and Etournay, Raphael
Subjects: [SDV]Life Sciences [q-bio], Mice, Myosin head, 0302 clinical medicine, Myosin, Inner ear, PHR1, MESH: Animals, Integral membrane protein, 0303 health sciences, Meromyosin, Cell biology, [SDV] Life Sciences [q-bio], Pleckstrin homology domain, Myosin VIIa, MESH: Membrane Proteins, Hair cell, MESH: Dyneins, Myosin light-chain kinase, MESH: Myosin Type I, Calmodulin, Molecular Sequence Data, macromolecular substances, Myosins, Biology, Models, Biological, MESH: Hair Cells, Auditory, Inner, Cell Line, Myosin Type I, 03 medical and health sciences, Myosin 1c, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, otorhinolaryngologic diseases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Hair Cells, Auditory, Inner, MESH: Humans, MESH: Molecular Sequence Data, MESH: Models, Biological, Dyneins, Membrane Proteins, Cell Biology, MESH: Myosins, Actin cytoskeleton, MESH: Cell Line, biology.protein, sense organs, 030217 neurology & neurosurgery
Abstract: International audience; By using the yeast two-hybrid technique, we identified a candidate protein ligand of the myosin 1c tail, PHR1, and found that this protein can also bind to the myosin VIIa tail. PHR1 is an integral membrane protein that contains a pleckstrin homology (PH) domain. Myosin 1c and myosin VIIa are two unconventional myosins present in the inner ear sensory cells. We showed that PHR1 immunoprecipitates with either myosin tail by using protein extracts from cotransfected HEK293 cells. In vitro binding assays confirmed that PHR1 directly interacts with these two myosins. In both cases the binding involves the PH domain. In vitro interactions between PHR1 and the myosin tails were not affected by the presence or absence of Ca2+ and calmodulin. Finally, we found that PHR1 is able to dimerise. As PHR1 is expressed in the vestibular and cochlear sensory cells, its direct interactions with the myosin 1c and VIIa tails are likely to play a role in anchoring the actin cytoskeleton to the plasma membrane of these cells. Moreover, as both myosins have been implicated in the mechanotransduction slow adaptation process that takes place in the hair bundles, we propose that PHR1 is also involved in this process.
Published: 2005
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27. Molecular mechanism of a frequent genetic form of deafness

Author: Christine Petit, Jean-Pierre Hardelin, and Vincent Michel
Subjects: Genetics, Mice, Knockout, Heterozygote, biology, Chromosomes, Human, Pair 13, Chromosome, General Medicine, Deafness, Chromosomes, Mammalian, Connexins, Connexin 26, Mice, otorhinolaryngologic diseases, biology.protein, Molecular mechanism, Connexin 30, Animals, Humans, sense organs, Gene, GJB6, Cochlea, Chromosome 13, Sequence Deletion
Abstract: To the Editor: The genes encoding the two major connexins of the cochlea are contiguous on human chromosome 13 (GJB2 and GJB6) and on mouse chromosome 14 (Cx26 and Cx30, respectively). Biallelic GJ...
Published: 2003

28. Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential

Author: Barbara Teubner, Jean-Pierre Hardelin, Klaus Jahnke, Claus Herberhold, Jörg Pesch, Christine Petit, Klaus Willecke, Vincent Michel, Martine Cohen-Salmon, Jürgen Lautermann, Goran Söhl, and Elke Winterhager
Subjects: medicine.medical_specialty, Endocochlear potential, Hearing loss, Degeneration (medical), Connexins, Mice, Internal medicine, otorhinolaryngologic diseases, Genetics, medicine, Connexin 30, Animals, Inner ear, Hearing Loss, Molecular Biology, Genetics (clinical), Cochlea, Alleles, Mice, Knockout, biology, General Medicine, Anatomy, Immunohistochemistry, Epithelium, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Apoptosis, biology.protein, medicine.symptom, GJB6
Abstract: The gap junction protein connexin30 (Cx30) is expressed in a variety of tissues that include epithelial and mesenchymal structures of the inner ear. We generated Cx30 (Gjb6) deficient mice by deletion of the Cx30 coding region. Homozygous mutants (Cx30((-/-))) were born at the expected Mendelian frequency, developed normally and were fertile. However, they exhibit a severe constitutive hearing impairment. From the age of hearing onset, these mice lack the electrical potential difference between the endolymphatic and perilymphatic compartments of the cochlea, i.e. the endocochlear potential, which plays a key role in the high sensitivity of the mammalian auditory organ. In addition, after postnatal day 18, the cochlear sensory epithelium starts to degenerate by cell apoptosis. This degeneration process is likely to account for the concomitant decrease of the endolymphatic potassium concentration and the aggravation of the hearing loss in adult Cx30((-/-)) mice. The Cx30 ((-/-)) phenotype thus reveals the critical role of Cx30 both in generating the endocochlear potential and for survival of the auditory hair cells after the onset of hearing. The Cx30 deficient mice may represent a valuable model to study the mechanism of the hearing loss in human patients carrying a homozygous deletion of the CX30 gene (del Castillo et al., 2002, New Engl. J. Med., 346, 243-249).
Published: 2002

29. Molecular genetics of hearing loss

Author: Jean-Pierre Hardelin, Jacqueline Levilliers, and Christine Petit
Subjects: Genetics, medicine.medical_specialty, Gap junction protein, Hearing loss, Tectorial membrane, Biology, Deafness, Human genetics, Connexins, Connexin 26, Mice, medicine.anatomical_structure, Molecular genetics, otorhinolaryngologic diseases, medicine, Animals, Humans, Hair cell, medicine.symptom, Gene, Cochlea
Abstract: ▪ Abstract Hereditary isolated hearing loss is genetically highly heterogeneous. Over 100 genes are predicted to cause this disorder in humans. Sixty loci have been reported and 24 genes underlying 28 deafness forms have been identified. The present epistemic stage in the realm consists in a preliminary characterization of the encoded proteins and the associated defective biological processes. Since for several of the deafness forms we still only have fuzzy notions of their pathogenesis, we here adopt a presentation of the various deafness forms based on the site of the primary defect: hair cell defects, nonsensory cell defects, and tectorial membrane anomalies. The various deafness forms so far studied appear as monogenic disorders. They are all rare with the exception of one, caused by mutations in the gene encoding the gap junction protein connexin26, which accounts for between one third to one half of the cases of prelingual inherited deafness in Caucasian populations.
Published: 2001

30. KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway

Author: Jean-Pierre Hardelin, Tatjana Kharkovets, Aziz El-Amraoui, Thomas J. Jentsch, Saaid Safieddine, Michaela Schweizer, Christine Petit, Universität Hamburg (UHH), Génétique des Déficits sensoriels, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie to T.J.J.
Subjects: Inferior colliculus, Auditory Pathways, Potassium Channels, [SDV]Life Sciences [q-bio], Hearing Loss, Sensorineural, Molecular Sequence Data, Sensory system, Biology, Mice, KCNQ2 Potassium Channel, otorhinolaryngologic diseases, medicine, Auditory system, Animals, Inner ear, Amino Acid Sequence, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, In Situ Hybridization, Genes, Dominant, Vestibular system, Mice, Inbred C3H, Multidisciplinary, KCNQ Potassium Channels, Lateral lemniscus, Brain, Immunohistochemistry, Microscopy, Electron, medicine.anatomical_structure, Potassium Channels, Voltage-Gated, Ear, Inner, COS Cells, Commentary, Neuroscience, KCNQ4
Abstract: Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal dominant form of progressive hearing loss in humans. In the mouse cochlea, the transcript has been found exclusively in the outer hair cells. By using specific antibodies, we now show that KCNQ4 is situated at the basal membrane of these sensory cells. In the vestibular organs, KCNQ4 is restricted to the type I hair cells and the afferent calyx-like nerve endings ensheathing these sensory cells. Several lines of evidence suggest that KCNQ4 underlies the I K,n and g K,L currents that have been described in the outer and type I hair cells, respectively, and that are already open at resting potentials. KCNQ4 is also expressed in neurons of many, but not all, nuclei of the central auditory pathway, and is absent from most other brain regions. It is present, e.g., in the cochlear nuclei, the nuclei of the lateral lemniscus, and the inferior colliculus. This is the first ion channel shown to be specifically expressed in a sensory pathway. Moreover, the expression pattern of KCNQ4 in the mouse auditory system raises the possibility of a central component in the DFNA2 hearing loss.
Published: 2000
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31. The human SOX11 gene: cloning, chromosomal assignment and tissue expression

Author: Jean-Pierre Hardelin, Catherine Gozé, Catherine Marsollier, Philippe Jay, Sylvie Taviaux, Philippe Berta, and Peter Koopman
Subjects: Male, Sex Determination Analysis, Molecular Sequence Data, Repressor, Gene Expression, Molecular cloning, Biology, Homology (biology), SOXC Transcription Factors, Mice, Gene mapping, Complementary DNA, Testis, Genetics, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Cloning, Molecular, Gene, Regulation of gene expression, Mammals, Genomic Library, Base Sequence, Sequence Homology, Amino Acid, High Mobility Group Proteins, Chromosome Mapping, Nuclear Proteins, Blotting, Northern, Sex-Determining Region Y Protein, DNA-Binding Proteins, Testis determining factor, Chromosomes, Human, Pair 2, Chickens, Transcription Factors
Abstract: The mammalian testis determining gene SRY contains an HMG box-related DNA binding motif. By analogy a family of genes related to SRY in the HMG domain have been called SOX (SRY box-related genes). We have cloned and characterized the human SOX11 gene using the partial cloning of both human and mouse SOX11 genes and mapped it to chromosome 2p25. The SOX11 sequence is strongly conserved with the chicken homologue and is related to SOX4. It contains several putative transcriptional either activator or repressor domains. SOX11 expression pattern is consistent with the hypothesis that this gene is important in the developing nervous system.
Published: 1995

32. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Author: Omar Akil, Didier Dulon, Samantha Papal, Vincent Michel, Paul Avan, Alice Emptoz, Aziz El-Amraoui, Olinda Alegria-Prévot, Sedigheh Delmaghani, Pranav Patni, Lawrence R. Lustig, Christine Petit, Alain Aghaie, Abdelaziz Tlili, Elise Pepermans, Yohan Bouleau, Saaid Safieddine, Margot Tertrais, Matteo Cortese, Philippe F.Y. Vincent, Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), University of California [San Francisco] (UC San Francisco), University of California (UC), Columbia University [New York], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), SP and MC benefited from fellowships from the Ministry of National Education, Research and Technology of France, and PP from the European Union’s Horizon 2020 Marie Sklodowska-Curie grant 665807. This work was supported by European Research Council (ERC) advanced grant 'Hair bundle' (ERC-2011-AdG 294570), the European Union Seventh Framework Programme under grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (light4deaf, ANR-15-RHUS-0001), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, FAUN Stiftung (Suchert Foundation), LABEX Life-senses (ANR-10-LABX-65), and a grant from the Fondation Pour l’Audition to DD (2015-APA Research Grant)., We thank Jean-Pierre Hardelin and Jacques Boutet de Monvel for critical reading of the manuscript., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), Neuroscience Institute-Université de Bordeaux ( UB ) -CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie du fruit et pathologie ( BFP ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique ( INRA ) -Université Sciences et Technologies - Bordeaux 1, Laboratoire Biochimie et Biologie Moléculaire ( LBBM ), Université Hassan II, Neuro-Dol ( Neuro-Dol ), Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), Comité Français de la Semoulerie Industrielle ( CFSI ), Génétique et physiologie de l'audition, This work was supported by European Research Council (ERC) advanced grant 'Hair bundle' (ERC-2011-AdG 294570), the European Union Seventh Framework Programme under grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (light4deaf, ANR-15-RHUS-0001), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, FAUN Stiftung (Suchert Foundation), LABEX Life-senses (ANR-10-LABX-65), and a grant from the Fondation Pour l’Audition to DD (2015-APA Research Grant)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER ( 2015 ), ANR-17-CE16-0017,HearInNoise,Surdité d’apparition tardive et progressive: de la physiopathologie à la thérapie ( 2017 ), ANR-11-IDEX-0004-02/10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE ( 2011 ), European Project : 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE ( 2012 ), European Project : 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH ( 2010 ), Neuroscience Institute-Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of California [San Francisco] (UCSF), University of California, Chaire Génétique et physiologie cellulaire, Oficjalska, Danuta, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, and Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID
Subjects: 0301 basic medicine, Calcium Channels, L-Type, Usher syndrome, PDZ domain, Cell Cycle Proteins, AMPA receptor, Ribbon synapse, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene therapy, Postsynaptic potential, Hair Cells, Auditory, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, otorhinolaryngologic diseases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptors, AMPA, Mice, Knockout, Gene Transfer Techniques, Membrane Proteins, General Medicine, Genetic Therapy, Dependovirus, medicine.disease, Cell biology, Cytoskeletal Proteins, Disease Models, Animal, Calcium channels, 030104 developmental biology, medicine.anatomical_structure, Knockout mouse, Synapses, Synaptopathy, Human medicine, Hair cell, [ SCCO ] Cognitive science, Carrier Proteins, Usher Syndromes, 030217 neurology & neurosurgery, Research Article, Neuroscience
Abstract: Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1(ex4-/-)) and postnatal hair cell-specific conditional (Clrn1(ex4fl/fl) Myo15-Cre(+/-)) knockout mice. Clrn1(ex4-/-) mice were profoundly deaf, whereas Clrn1(ex4fl/fl) Myo15-Cre(+/-) mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and Ca(V)1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic Ca(V)1.3 Ca2+ channel complex via the Ca-V beta(2) auxiliary subunit and the PDZ domain-containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus-mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1(ex4fl/fl) Myo15-Cre(+/-) mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients.
Published: 2018
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33. Mouse Models of Developmental Genetic Disease

Author: Robert S. Krauss and Robert S. Krauss
Subjects: Abnormalities, Human, Mice as laboratory animals, Diseases--Animal models, Mice
Abstract: Approximately three percent of newborn humans have congenital anomalies with significant cosmetic and/or functional consequences. Much of our ability to understand what has gone awry in these birth defects rests with development of animal models for them; the mouse has emerged as the model organism of choice for these studies. This volume reviews mouse models of specific developmental genetic diseases, including neural tube defects; cleft lip and/or palate; congenital heart disease; ciliopathies; hereditary deafness and others to provide conceptual insight into congenital anomalies generally. The interplay between clinical observation and murine model systems is expected to yield deep insight into mammalian developmental processes and the emergence of effective preventive and/or therapeutic strategies. - Provides busy clinical and basic science researchers a one-stop overview and synthesis of the latest research findings and contemporary thought in the area - Allows researchers to compare and contrast disease models and also to learn about what models have been developed for large-scale distribution - Allows researchers to evaluate basic differences in mouse and human biology and propose alternate pathways and possible gene interactions of the disease
Published: 2008

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33 results on '"Jean-Pierre Hardelin"'

1. Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety

2. Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane

3. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

4. Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells

5. Mutations in CDC14A , Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness

6. Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

7. Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice

8. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice

9. Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids

10. Cochlear outer hair cells undergo an apical circumference remodeling constrained by the hair bundle shape

11. Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells

12. Stereocilin-deficient mice reveal the origin of cochlear waveform distortions

13. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity

14. A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth

15. Molecular Characterization of the Ankle-Link Complex in Cochlear Hair Cells and Its Role in the Hair Bundle Functioning

16. Connexin30 deficiency causes instrastrial fluid–blood barrier disruption within the cochlear stria vascularis

17. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

18. Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly

19. The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells

20. EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness

21. Unconventional Myosin VIIA Is a Novel A-kinase-anchoring Protein

22. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness

23. Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

24. Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells

25. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

26. PHR1, an integral membrane protein of the inner ear sensory cells, directly interacts with myosin 1c and myosin VIIa

27. Molecular mechanism of a frequent genetic form of deafness

28. Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential

29. Molecular genetics of hearing loss

30. KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway

31. The human SOX11 gene: cloning, chromosomal assignment and tissue expression

32. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

33. Mouse Models of Developmental Genetic Disease

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33 results on '"Jean-Pierre Hardelin"'

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