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.
Highlights
The process of hearing requires the transduction of sound waveinduced mechanical energy into neuronal signals
During a recent phenotype-driven ENU-mutagenesis screen undertaken at the MRC Harwell Institute, pedigree MPC169 was identified as containing mice with hearing impairment (Potter et al, 2016)
We demonstrate that clarin-2 is required for the maintenance of stereocilia bundle morphology, and show that its loss leads to decreased mechano-electrical transduction and progressive hearing impairment
Summary
The process of hearing requires the transduction of sound waveinduced mechanical energy into neuronal signals. This process is achieved by the mechanosensitive inner ear hair cells located in the cochlea. These specialized sensory cells, named inner hair cells (IHCs) and outer hair cells (OHCs), have an array of actinfilled stereocilia protruding from their apical surface. Each hair cell stereocilia bundle is arranged as 3–4 rows in a highly ordered “staircase-like” structure, which is essential for function. In response to sound-induced fluid movement within the inner ear, hair cell bundles are deflected towards the tallest stereocilia
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