Giese Arnaud P J, Tang Yi-Quan, Sinha Ghanshyam P, Bowl Michael R, Goldring Adam C, Parker Andrew, Freeman Mary J, Brown Steve D M, Riazuddin Saima, Fettiplace Robert, Schafer William R, Frolenkov Gregory I, Ahmed Zubair M
Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.
Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
Nat Commun. 2017 Jun 29;8(1):43. doi: 10.1038/s41467-017-00061-1.
Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of both Cib2 mutants. Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.Inner ear hair cells detect sound through deflection of stereocilia that harbor mechanically-gated channels. Here the authors show that protein responsible for Usher syndrome, CIB2, interacts with these channels and is essential for their function and hearing in mice.
内耳毛细胞通过静纤毛的偏转来检测声音，静纤毛是呈梯度高度排列成行的微绒毛样突起。钙和整合素结合蛋白2对听力至关重要，并定位于静纤毛，但它的确切功能尚不清楚。在这里，我们对两个突变小鼠品系进行了表征，一个缺失钙和整合素结合蛋白2，另一个携带与人类耳聋相关的Cib2突变，并表明两者均耳聋，且听觉毛细胞中无机械转导现象，尽管存在开启机械转导通道的顶连接。此外，在两个Cib2突变体的毛细胞束中，进行机械转导的较短排静纤毛过度生长。此外，我们报告钙和整合素结合蛋白2与毛细胞机械转导复合体的组分TMC1和TMC2结合，并且这些相互作用被导致耳聋的Cib2突变破坏。我们得出结论，钙和整合素结合蛋白2是机械转导通道正常运作所必需的，并且参与限制转导静纤毛的生长。内耳毛细胞通过含有机械门控通道的静纤毛的偏转来检测声音。本文作者表明，导致Usher综合征的蛋白质CIB2与这些通道相互作用，并且对其功能和小鼠听力至关重要。
