In the mammalian cochlea, the planar cell polarity (PCP) pathway aligns hair cell orientation along the plane of the sensory epithelium. Concurrently, multiple cell intrinsic planar polarity (referred to as iPCP) modules mediate planar polarization of the hair cell apical cytoskeleton, including the kinocilium and the V-shaped hair bundle essential for mechanotransduction. How PCP and iPCP are coordinated during development and the roles of Wnt ligands in this process remain unresolved. Here we show that genetic blockade of Wnt secretion in the cochlear epithelium resulted in a shortened cochlear duct and misoriented and misshapen hair bundles. Mechanistically, Wnts stimulate Gi activity by regulating the localization of Daple, a guanine nucleotide exchange factor (GEF) for Gαi. In turn, the Gβγ complex signals through phosphoinositide 3-kinase (PI3K) to regulate kinocilium positioning and asymmetric localizations of a subset of core PCP proteins, thereby coordinating PCP and iPCP. Thus, our results identify a putative Wnt/heterotrimeric G protein/PI3K pathway for PCP regulation.

中文翻译：

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Wnts 通过异三聚体 G 蛋白和 PI3K 信号传导调节平面细胞极性

在哺乳动物耳蜗中，平面细胞极性（PCP）通路沿着感觉上皮平面对齐毛细胞方向。同时，多个细胞固有平面极性（称为 iPCP）模块介导毛细胞顶端细胞骨架的平面极化，包括机械转导必需的运动纤毛和 V 形毛束。PCP 和 iPCP 在发育过程中如何协调以及 Wnt 配体在此过程中的作用仍未解决。在这里，我们发现，耳蜗上皮中 Wnt 分泌的基因阻断导致耳蜗导管缩短以及毛束定向和畸形。从机制上讲，Wnts 通过调节 Daple（Gαi 的鸟嘌呤核苷酸交换因子 (GEF)）的定位来刺激 Gi 活性。反过来，Gβγ 复合物通过磷酸肌醇 3 激酶 (PI3K) 发出信号，调节动纤毛定位和核心 PCP 蛋白子集的不对称定位，从而协调 PCP 和 iPCP。因此，我们的结果确定了 PCP 调节的假定 Wnt/异三聚体 G 蛋白/PI3K 途径。