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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Main Authors: 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
Format: Article
Language:English
Published: Wiley 2019-09-01
Series:EMBO Molecular Medicine
Subjects:
Online Access:https://doi.org/10.15252/emmm.201910288
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language English
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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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spelling 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