Dunbar, LA;
Patni, P;
Aguilar, C;
Mburu, P;
Corns, L;
Wells, HR;
Delmaghani, S;
... Bowl, MR; + view all
(2019)
Clarin-2 is essential for hearing by maintaining stereocilia integrity and function.
EMBO Molecular Medicine
, Article e10288. 10.15252/emmm.201910288.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Clarin-2 is essential for hearing by maintaining stereocilia integrity and function |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.201910288 |
| Publisher version: | https://doi.org/10.15252/emmm.201910288 |
| Language: | English |
| Additional information: | Copyright © 2019 The Authors. Published under the terms of the CC BY 4.0 license. |
| Keywords: | hair cells, mechanotransduction, mouse models, mutagenesis, stereocilia |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10080901 |
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