Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes
Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes
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DOI：
10.1172/jci60405
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发表时间：
2011-12-01
影响因子：
15.9
通讯作者：
Griffith, Andrew J.
中科院分区：
文献类型：
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作者：
Kawashima, Yoshiyuki;Geleoc, Gwenaelle S. G.;Griffith, Andrew J.
内耳毛细胞将声音、重力和头部运动等机械刺激转化为电信号。这种机械转导过程是由毛细胞立体纤毛尖端附近的阳离子通道打开而开始的。由于这些离子通道的身份尚不清楚，并且编码跨膜通道样1 （TMC1）的基因突变会导致小鼠和人类的听力损失而没有前庭功能障碍，因此我们研究了TMC1和密切相关的Tmc2对小鼠机械转导的贡献。我们发现Tmc1和Tmc2在小鼠前庭和耳蜗毛细胞中表达，gfp标记的TMC蛋白定位在立体纤毛尖端附近。Tmc2在出生后早期小鼠耳蜗毛细胞中的表达是短暂的，但在前庭毛细胞中持续表达。靶向缺失Tmc1的小鼠（Tmc1(Delta) a小鼠）耳聋，而缺失Tmc2的小鼠（Tmc2（Delta）小鼠）表型正常，Tmc1(Delta)Tmc2（Delta）小鼠具有严重的前庭功能障碍、耳聋和结构正常的毛细胞，缺乏所有机械转导活性。外源性TMC1或TMC2的表达可挽救TMC1 (Delta) TMC2 （Delta）突变毛细胞的机械转导。我们的研究结果表明，TMC1和TMC2是毛细胞机械转导所必需的，可能是机械转导复合物的组成部分。我们的数据还表明，前庭毛细胞中持续的TMC2表达可能会保护由TMC1突变引起的听力损失患者的前庭功能。
Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1(Delta) A mice) were deaf and those with a deletion of Tmc2 (Tmc2(Delta) mice) were phenotypically normal, Tmc1(Delta)Tmc2(Delta) mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1(Delta)Tmc2(Delta) mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations.