Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 9, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201910288
Keywords
hair cells; mechanotransduction; mouse models; mutagenesis; stereocilia
Categories
Funding
- Medical Research Council [MC_U142684175, MC_UP_1503/2]
- Wellcome Trust [102892]
- French National Research Agency (ANR) as part of the second Investissements d'Avenir programme (light4deaf) [ANR-15-RHUS-0001]
- LHW-Stiftung
- ANR-HearInNoise [ANR-17-CE16-0017]
- NIDCD/NIH [R01DC013817]
- NIMH/NIH [R24MH114815]
- Hearing Restoration Program of the Hearing Health Foundation
- Action on Hearing Loss PhD studentship - National Institute for Health Research University College London Hospitals Biomedical Research Centre
- European Union's Horizon 2020 Marie Sklodowska-Curie grant [665807]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE16-0017] Funding Source: Agence Nationale de la Recherche (ANR)
- MRC [MC_U142684175, MC_UP_1503/2, MC_UP_1502/1] Funding Source: UKRI
Ask authors/readers for more resources
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 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available