Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain
Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain
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DOI：
10.1242/dev.060061
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发表时间：
2011-04-15
期刊：
影响因子：
4.6
通讯作者：
Mueller, Ulrich
中科院分区：
文献类型：
--
作者：
Webb, Stuart W.;Grillet, Nicolas;Mueller, Ulrich
原钙粘蛋白15（PCDH 15）在内耳的毛细胞和视网膜的光感受器中表达。PCDH 15中的突变导致Usher综合征（双盲）和隐性耳聋。在毛细胞发育过程中，PCDH 15定位于细胞外连接，将静纤毛和动纤毛连接成束并调节其形态发生。在成熟的毛细胞中，PCDH 15是尖端连接的一个组成部分，其门控机械转导通道。PCDH 15以细胞质结构域不同的几种亚型表达，这表明选择性剪接调节毛细胞中的PCDH 15功能。为了测试该模型，我们产生了三种小鼠品系，每种都缺乏三种突出的PCDH 15同种型（CD 1、CD 2和CD 3）中的一种。令人惊讶的是，缺乏PCDH 15-CD 1和PCDH 15-CD 3的小鼠形成正常的毛束和尖端连接，并保持听力功能。在缺乏PCDH 15-CD 2的小鼠中也存在尖端连接。然而，PCDH 15-CD 2缺陷小鼠是耳聋的，缺乏动纤毛连接，并具有异常极化的毛束。平面细胞极性（PCP）蛋白正常分布在突变体的感觉上皮细胞，表明PCDH 15-CD 2的PCP组件的下游行为，以控制极性。尽管不存在动纤毛连接，但前庭功能在PCDH 15-CD 2突变体中令人惊讶地完整。我们的研究结果揭示了一个必不可少的作用PCDH 15-CD 2在形成动纤毛链接和毛束极化，并表明，几个PCDH 15亚型可以冗余地在尖端链接。
Protocadherin 15 (PCDH15) is expressed in hair cells of the inner ear and in photoreceptors of the retina. Mutations in PCDH15 cause Usher Syndrome (deaf-blindness) and recessive deafness. In developing hair cells, PCDH15 localizes to extracellular linkages that connect the stereocilia and kinocilium into a bundle and regulate its morphogenesis. In mature hair cells, PCDH15 is a component of tip links, which gate mechanotransduction channels. PCDH15 is expressed in several isoforms differing in their cytoplasmic domains, suggesting that alternative splicing regulates PCDH15 function in hair cells. To test this model, we generated three mouse lines, each of which lacks one out of three prominent PCDH15 isoforms (CD1, CD2 and CD3). Surprisingly, mice lacking PCDH15-CD1 and PCDH15-CD3 form normal hair bundles and tip links and maintain hearing function. Tip links are also present in mice lacking PCDH15-CD2. However, PCDH15-CD2-deficient mice are deaf, lack kinociliary links and have abnormally polarized hair bundles. Planar cell polarity (PCP) proteins are distributed normally in the sensory epithelia of the mutants, suggesting that PCDH15-CD2 acts downstream of PCP components to control polarity. Despite the absence of kinociliary links, vestibular function is surprisingly intact in the PCDH15-CD2 mutants. Our findings reveal an essential role for PCDH15-CD2 in the formation of kinociliary links and hair bundle polarization, and show that several PCDH15 isoforms can function redundantly at tip links.