Clarin-2 is essential for hearing by maintaining stereocilia integrity and function
Clarin-2 is essential for hearing by maintaining stereocilia integrity and function
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DOI：
10.15252/emmm.201910288
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发表时间：
2019-08-26
影响因子：
11.1
通讯作者：
Bowl, Michael R.
中科院分区：
文献类型：
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作者：
Dunbar, Lucy A.;Patni, Pranav;Bowl, Michael R.
听觉依赖于耳蜗毛细胞顶面富含肌动蛋白的静纤毛束中的机械门控离子通道。我们对声音感受结构的形成和维持机制的了解是有限的。利用小鼠大规模正向遗传筛选、基因组定位和基因互补试验，我们鉴定了Clrn 2为一个新的耳聋基因。Clrn 2（单簧管/单簧管）小鼠（p.Trp4* 突变）表现出进行性早发性听力损失，没有明显的视网膜缺陷。利用英国生物银行研究的数据，我们可以证明CLRN 2与人类非综合征性进行性听力损失有关。我们深入的形态学，分子和功能研究证实，虽然它不是耳蜗感觉毛细胞静纤毛束的初始形成所必需的，但clarin-2对于维持正常的束完整性和功能至关重要。在分化中的毛束中，缺乏clarin-2导致机械-电转导的损失，随后是转导静纤毛的选择性进行性损失。总之，我们的研究结果表明clarin-2在哺乳动物听力中的关键作用，为机械电转导和静纤毛维持之间的相互作用提供了见解。
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.