Clarin-2 is essential for hearing by maintaining stereocilia integrity and function
JournalEMBO Molecular Medicine
PublisherBlackwell Publishing Ltd
MetadataShow full item record
AbstractHearing 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. Copyright 2019 The Authors.
SponsorsThis 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.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85071788636&doi=10.15252%2femmm.201910288&partnerID=40&md5=4e39d85d894899f62e248f973f95de78; http://hdl.handle.net/10713/10852
- A short splice form of Xin-actin binding repeat containing 2 (XIRP2) lacking the Xin repeats is required for maintenance of stereocilia morphology and hearing function.
- Authors: Francis SP, Krey JF, Krystofiak ES, Cui R, Nanda S, Xu W, Kachar B, Barr-Gillespie PG, Shin JB
- Issue date: 2015 Feb 4
- Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness.
- Authors: Carlton AJ, Halford J, Underhill A, Jeng JY, Avenarius MR, Gilbert ML, Ceriani F, Ebisine K, Brown SDM, Bowl MR, Barr-Gillespie PG, Marcotti W
- Issue date: 2021 Feb
- Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner.
- Authors: Kazmierczak M, Kazmierczak P, Peng AW, Harris SL, Shah P, Puel JL, Lenoir M, Franco SJ, Schwander M
- Issue date: 2017 Mar 29
- Methionine sulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells.
- Authors: Kwon TJ, Cho HJ, Kim UK, Lee E, Oh SK, Bok J, Bae YC, Yi JK, Lee JW, Ryoo ZY, Lee SH, Lee KY, Kim HY
- Issue date: 2014 Mar 15
- Mutations of the mouse ELMO domain containing 1 gene (Elmod1) link small GTPase signaling to actin cytoskeleton dynamics in hair cell stereocilia.
- Authors: Johnson KR, Longo-Guess CM, Gagnon LH
- Issue date: 2012