Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function
Abstract 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...
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Format: | Article |
Language: | English |
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Wiley
2019-09-01
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Series: | EMBO Molecular Medicine |
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Online Access: | https://doi.org/10.15252/emmm.201910288 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lucy A Dunbar Pranav Patni Carlos Aguilar Philomena Mburu Laura Corns Helena RR Wells Sedigheh Delmaghani Andrew Parker Stuart Johnson Debbie Williams Christopher T Esapa Michelle M Simon Lauren Chessum Sherylanne Newton Joanne Dorning Prashanthini Jeyarajan Susan Morse Andrea Lelli Gemma F Codner Thibault Peineau Suhasini R Gopal Kumar N Alagramam Ronna Hertzano Didier Dulon Sara Wells Frances M Williams Christine Petit Sally J Dawson Steve DM Brown Walter Marcotti Aziz El‐Amraoui Michael R Bowl |
spellingShingle |
Lucy A Dunbar Pranav Patni Carlos Aguilar Philomena Mburu Laura Corns Helena RR Wells Sedigheh Delmaghani Andrew Parker Stuart Johnson Debbie Williams Christopher T Esapa Michelle M Simon Lauren Chessum Sherylanne Newton Joanne Dorning Prashanthini Jeyarajan Susan Morse Andrea Lelli Gemma F Codner Thibault Peineau Suhasini R Gopal Kumar N Alagramam Ronna Hertzano Didier Dulon Sara Wells Frances M Williams Christine Petit Sally J Dawson Steve DM Brown Walter Marcotti Aziz El‐Amraoui Michael R Bowl Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function EMBO Molecular Medicine hair cells mechanotransduction mouse models mutagenesis stereocilia |
author_facet |
Lucy A Dunbar Pranav Patni Carlos Aguilar Philomena Mburu Laura Corns Helena RR Wells Sedigheh Delmaghani Andrew Parker Stuart Johnson Debbie Williams Christopher T Esapa Michelle M Simon Lauren Chessum Sherylanne Newton Joanne Dorning Prashanthini Jeyarajan Susan Morse Andrea Lelli Gemma F Codner Thibault Peineau Suhasini R Gopal Kumar N Alagramam Ronna Hertzano Didier Dulon Sara Wells Frances M Williams Christine Petit Sally J Dawson Steve DM Brown Walter Marcotti Aziz El‐Amraoui Michael R Bowl |
author_sort |
Lucy A Dunbar |
title |
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function |
title_short |
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function |
title_full |
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function |
title_fullStr |
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function |
title_full_unstemmed |
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function |
title_sort |
clarin‐2 is essential for hearing by maintaining stereocilia integrity and function |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2019-09-01 |
description |
Abstract 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 Clrn2clarinet/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 in‐depth 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. |
topic |
hair cells mechanotransduction mouse models mutagenesis stereocilia |
url |
https://doi.org/10.15252/emmm.201910288 |
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doaj-aa32f3d7e38046868ba58a51eb9e8d122021-08-02T04:57:29ZengWileyEMBO Molecular Medicine1757-46761757-46842019-09-01119n/an/a10.15252/emmm.201910288Clarin‐2 is essential for hearing by maintaining stereocilia integrity and functionLucy A Dunbar0Pranav Patni1Carlos Aguilar2Philomena Mburu3Laura Corns4Helena RR Wells5Sedigheh Delmaghani6Andrew Parker7Stuart Johnson8Debbie Williams9Christopher T Esapa10Michelle M Simon11Lauren Chessum12Sherylanne Newton13Joanne Dorning14Prashanthini Jeyarajan15Susan Morse16Andrea Lelli17Gemma F Codner18Thibault Peineau19Suhasini R Gopal20Kumar N Alagramam21Ronna Hertzano22Didier Dulon23Sara Wells24Frances M Williams25Christine Petit26Sally J Dawson27Steve DM Brown28Walter Marcotti29Aziz El‐Amraoui30Michael R Bowl31Mammalian Genetics Unit MRC Harwell Institute Harwell UKDéficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris FranceMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKDepartment of Biomedical Science University of Sheffield Sheffield UKDepartment of Twin Research & Genetic Epidemiology King's College London London UKDéficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris FranceMammalian Genetics Unit MRC Harwell Institute Harwell UKDepartment of Biomedical Science University of Sheffield Sheffield UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKMammalian Genetics Unit MRC Harwell Institute Harwell UKGénétique et Physiologie de l'Audition Institut Pasteur INSERM UMR‐S 1120 Collège de France Sorbonne Universités Paris FranceMary Lyon Centre MRC Harwell Institute Harwell UKLaboratoire de Neurophysiologie de la Synapse Auditive Université de Bordeaux Bordeaux FranceDepartment of Otolaryngology – Head and Neck Surgery University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland OH USADepartment of Otolaryngology – Head and Neck Surgery University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland OH USADepartment of Otorhinolaryngology Head and Neck Surgery, Anatomy and Neurobiology and Institute for Genome Sciences University of Maryland School of Medicine Baltimore MD USALaboratoire de Neurophysiologie de la Synapse Auditive Université de Bordeaux Bordeaux FranceMary Lyon Centre MRC Harwell Institute Harwell UKDepartment of Twin Research & Genetic Epidemiology King's College London London UKGénétique et Physiologie de l'Audition Institut Pasteur INSERM UMR‐S 1120 Collège de France Sorbonne Universités Paris FranceUCL Ear Institute University College London London UKMammalian Genetics Unit MRC Harwell Institute Harwell UKDepartment of Biomedical Science University of Sheffield Sheffield UKDéficits Sensoriels Progressifs Institut Pasteur INSERM UMR‐S 1120 Sorbonne Universités Paris FranceMammalian Genetics Unit MRC Harwell Institute Harwell UKAbstract 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 Clrn2clarinet/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 in‐depth 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.https://doi.org/10.15252/emmm.201910288hair cellsmechanotransductionmouse modelsmutagenesisstereocilia |