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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells
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Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells

机译：Noddy，一种在protocadherin-15中带有错义突变的小鼠，揭示了破坏内耳毛细胞中尖端连接钙粘着蛋白之间关键相互作用位点的影响

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In hair cells of the inner ear, sound or head movement increases tension in fine filaments termed tip links, which in turn convey force to mechanosensitive ion channels to open them. Tip links are formed by a tetramer of two cadherin proteins: protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which have 11 and 27 extracellular cadherin (EC) repeats, respectively. Mutations in either protein cause inner ear disorders in mice and humans. We showed recently that these two cadherins bind tip-to-tip in a "handshake" mode that involves the EC1 and EC2 repeats of both proteins. However, a paucity of appropriate animal models has slowed our understanding both of the interaction and of how mutations of residues within the predicted interface compromise tip link integrity. Here, we present noddy, a new mouse model for hereditary deafness. Identified in a forward genetic screen, noddy homozygotes lack inner ear function. Mapping and sequencing showed that noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of PCDH15. Residue I108 interacts with CDH23 EC2 in the handshake and its mutation impairs the interaction in vitro. The noddy mutation allowed us to determine the consequences of blocking the handshake in vivo: tip link formation and bundle morphology are disrupted, and mechanotransduction channels fail to remain open at rest. These results offer new insights into the interaction between PCDH15 and CDH23 and help explain the etiology of human deafness linked to mutations in the tip-link interface. ? 2013 the authors.
机译：在内耳的毛细胞中，声音或头部的运动会增加细丝中的张力，这些细丝称为尖端连接，进而将力传递至机械敏感离子通道以打开它们。尖端连接是由两种钙粘蛋白的四聚体形成的：原钙粘蛋白15（PCDH15）和钙粘蛋白23（CDH23），它们分别具有11和27个细胞外钙粘蛋白（EC）重复序列。任一种蛋白质的突变都会在小鼠和人类中引起内耳疾病。我们最近显示，这两种钙粘蛋白在“握手”模式下端对端结合，涉及两种蛋白的EC1和EC2重复序列。然而，缺乏适当的动物模型减慢了我们对相互作用以及预测界面内残基突变如何损害末端连接完整性的理解。在这里，我们提出点头，一种遗传性耳聋的新小鼠模型。在向前的遗传筛查中发现，结节性纯合子缺乏内耳功能。定位和测序表明，结节突变小鼠在PCDH15的EC1重复序列中具有异亮氨酸至天冬酰胺（I108N）突变。残基I108在握手过程中与CDH23 EC2相互作用，其突变会削弱体外的相互作用。点头突变使我们能够确定在体内阻断握手的后果：尖端连接的形成和束形态被破坏，机械传导通道无法保持静止。这些结果为PCDH15和CDH23之间的相互作用提供了新的见解，并有助于解释与提示链接界面突变相关的人耳聋的病因。 ？ 2013作者。

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