Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function
In: EMBO Molecular Medicine EMBO Molecular Medicine, Wiley Open Access, 2019, 11 (9), pp.e10288. ⟨10.15252/emmm.201910288⟩, Jg. 11 (2019), Heft 9, S. n/a-n/a
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Zugriff:
International audience; Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2 clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our indepth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.
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Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function
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| Autor/in / Beteiligte Person: | El-Amraoui, Aziz ; Johnson, Stuart L. ; Petit, Christine ; Simon, Michelle ; Jeyarajan, Prashanthini ; Chessum, Lauren ; Bowl, Michael R. ; Newton, Sherylanne ; Lelli, Andrea ; Helena Rr Wells ; Frances M K Williams ; Parker, Andrew ; Dorning, Joanne ; Dulon, Didier ; Morse, Susan ; Gopal, Suhasini R. ; Steve D.M. Brown ; Delmaghani, Sedigheh ; Mburu, Philomena ; Esapa, Christopher T. ; Hertzano, Ronna ; Wells, Sara ; Williams, Debbie ; Aguilar, Carlos A. ; Alagramam, Kumar N. ; Patni, Pranav ; Peineau, Thibault ; Marcotti, Walter ; Corns, Laura F. ; Dawson, Sally J. ; Codner, Gemma F. ; Lucy A Dunbar ; MRC Harwell Institute [UK] ; Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, PathoPhysiology and Therapy ; Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU) ; University of Sheffield [Sheffield] ; King‘s College London ; Génétique et Physiologie de l'Audition ; Hines VA Medical Center [USA] ; Chaire Génétique et physiologie cellulaire ; Collège de France (CdF (institution)) ; Mary Lyon Centre, MRC Harwell Institute ; Neurophysiologie de la Synapse Auditive ; Neuroscience Institute-Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM) ; University Hospitals Case Medical Center (CLEVELAND - UHCMC) ; University Hospitals Case Medical Center ; University of Maryland School of Medicine ; University of Maryland System ; University College of London [London] (UCL) ; This work was supported by: Medical Research Council (MC_U142684175 to S.D.M.B. and MC_UP_1503/2 to M.R.B), Wellcome Trust (102892 to W.M.) ; the French National Research Agency (ANR) as part of the second 'Investissements d'Avenir' programme (light4deaf, ANR-15-RHUS-0001) and LHW-Stiftung (to C.P. & A.E.) ; ANR-HearInNoise-(ANR-17-CE16-0017 to A.E.) ; NIDCD/NIH (R01DC013817), NIMH/NIH (R24MH114815) and the Hearing Restoration Program of the Hearing Health Foundation (to R.H.) ; and an Action on Hearing Loss PhD studentship (to F.W. and S.Da.), which was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. L.D. is a Medical Research Council PhD student. P.P. benefited from a fellowship from the European Union's Horizon 2020 Marie Sklodowska-Curie grant No 665807. S.L.J. is a Royal Society University Research Fellow. ; 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) ; European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015) ; 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 ; Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute ; EL-AMRAOUI, Aziz ; ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS -, VALID ; Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie - - HearInNoise2017 - ANR-17-CE16-0017 - AAPG2017 -, VALID ; Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 -, VALID |
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| Zeitschrift: | EMBO Molecular Medicine EMBO Molecular Medicine, Wiley Open Access, 2019, 11 (9), pp.e10288. ⟨10.15252/emmm.201910288⟩, Jg. 11 (2019), Heft 9, S. n/a-n/a |
| Veröffentlichung: | HAL CCSD, 2019 |
| Medientyp: | unknown |
| ISSN: | 1757-4676 (print) ; 1757-4684 (print) |
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