A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth
A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth
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DOI：
10.1242/dev.012922
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发表时间：
2008-04-15
期刊：
影响因子：
4.6
通讯作者：
Petit, Christine
中科院分区：
文献类型：
--
作者：
Lefevre, Gaelle;Michel, Vincent;Petit, Christine
毛束的平面极性和阶梯状结构对内耳感觉细胞的机械电传导功能至关重要。编码肌球蛋白VIIa、harmonin、钙粘蛋白23、原钙粘蛋白15或sans的基因突变导致人类I型Usher综合征（USH 1，特征为先天性耳聋、前庭功能障碍和导致失明的色素性视网膜炎）和小鼠的毛束紊乱。USH 1蛋白是否参与常见的毛束形态发生过程尚不清楚。在这里，我们表明，五个USH 1遗传形式的小鼠模型共享毛束形态缺陷。早在胚胎第17天就检测到毛束碎片和定向错误（25-52平均动纤毛偏差，取决于突变体）。静纤毛行的异常差异伸长发生在出生后的第一天。在新兴的毛束，肌球蛋白VIIa，肌动蛋白结合的膜下蛋白harmonin-b，和interstereocilia-kinocilium横向链接组件钙粘蛋白23和原钙粘蛋白15，都集中在静纤毛提示，按照他们已知的体外相互作用。出生后不久，harmonin-b从静纤毛的顶端转移到顶端连接的上端，其中还包括钙粘蛋白23和原钙粘蛋白15。这种位置的变化并没有发生在缺乏钙粘蛋白23或原钙粘蛋白15的小鼠。我们认为，张力施加到早期的横向链接和尖端链接，这两者都可以通过harmonin-b锚定到肌动蛋白丝，发挥了关键作用，在毛束凝聚力和正确的方向为前者，并在立体纤毛伸长为后者。
The planar polarity and staircase-like pattern of the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15 or sans cause Usher syndrome type I (USH1, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans and hair bundle disorganization in mice. Whether the USH1 proteins are involved in common hair bundle morphogenetic processes is unknown. Here, we show that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-52 mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17. Abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin 23 and protocadherin 15, all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth, harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin 23 and protocadherin 15. This positional change did not occur in mice deficient for cadherin 23 or protocadherin 15. We suggest that tension forces applied to the early lateral links and to the tip link, both of which can be anchored to actin filaments via harmonin-b, play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter.