Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear
Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear
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DOI：
10.1242/dev.074229
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发表时间：
2012-10-15
期刊：
影响因子：
4.6
通讯作者：
Montcouquiol, Mireille
中科院分区：
文献类型：
--
作者：
Giese, Arnaud P.;Ezan, Jerome;Montcouquiol, Mireille
Vangl2是在不同物种的多种组织中控制平面细胞极性建立的中心蛋白之一。先前的研究表明，Vangl2蛋白定位于特定的细胞内微结构域对其功能至关重要。然而，控制Vangl2在细胞内运输的分子机制在很大程度上是未知的。在这里，我们确定Gipc1（GAIP C-末端相互作用蛋白1）作为一个新的相互作用Vangl2，我们表明，肌球蛋白VI-Gipc1蛋白复合物可以调节Vangl2交通异源细胞。此外，我们表明，在MyoVI突变小鼠的耳蜗，Vangl2在膜上的存在增加，并且毛细胞中Gipc1功能的破坏导致成熟缺陷，包括毛束方向和完整性的缺陷。最后，受激发射损耗显微术和GFP-Vangl2的过表达显示Vangl2在支持细胞侧富集，邻近毛细胞的近端膜。总之，这些结果表明Gipc1在静纤毛束和细胞极化的发展中发挥了广泛的作用，并表明在出生后早期耳蜗上皮中观察到的Vangl2的强烈不对称性主要是“组织”极性读出。
Vangl2 is one of the central proteins controlling the establishment of planar cell polarity in multiple tissues of different species. Previous studies suggest that the localization of the Vangl2 protein to specific intracellular microdomains is crucial for its function. However, the molecular mechanisms that control Vangl2 trafficking within a cell are largely unknown. Here, we identify Gipc1 (GAIP C-terminus interacting protein 1) as a new interactor for Vangl2, and we show that a myosin VI-Gipc1 protein complex can regulate Vangl2 traffic in heterologous cells. Furthermore, we show that in the cochlea of MyoVI mutant mice, Vangl2 presence at the membrane is increased, and that a disruption of Gipc1 function in hair cells leads to maturation defects, including defects in hair bundle orientation and integrity. Finally, stimulated emission depletion microscopy and overexpression of GFP-Vangl2 show an enrichment of Vangl2 on the supporting cell side, adjacent to the proximal membrane of hair cells. Altogether, these results indicate a broad role for Gipc1 in the development of both stereociliary bundles and cell polarization, and suggest that the strong asymmetry of Vangl2 observed in early postnatal cochlear epithelium is mostly a 'tissue' polarity readout.