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Wnts 通过异三聚体 G 蛋白和 PI3K 信号通路调节平面细胞极性。

Wnts regulate planar cell polarity via heterotrimeric G protein and PI3K signaling.

机构信息

Department of Cell Biology, University of Virginia Health System, Charlottesville, VA.

出版信息

J Cell Biol. 2020 Oct 5;219(10). doi: 10.1083/jcb.201912071.

Abstract

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.

摘要

在哺乳动物耳蜗中,平面细胞极性(PCP)途径沿感觉上皮的平面排列毛细胞的方向。同时,多个细胞内平面极性(称为 iPCP)模块介导毛细胞顶端细胞骨架的平面极化,包括动纤毛和 V 形毛束,这对于机械转导至关重要。PCP 和 iPCP 在发育过程中是如何协调的,以及 Wnt 配体在这个过程中的作用仍未解决。在这里,我们表明,在耳蜗上皮细胞中遗传阻断 Wnt 分泌会导致耳蜗管缩短,毛束方向错误和畸形。在机制上,Wnts 通过调节鸟嘌呤核苷酸交换因子(GEF)Daple 的定位来刺激 Gi 活性,Daple 是 Gαi 的 GEF。反过来,Gβγ 复合物通过磷酸肌醇 3-激酶(PI3K)信号传导调节动纤毛的定位和一组核心 PCP 蛋白的不对称定位,从而协调 PCP 和 iPCP。因此,我们的结果确定了一个假定的 Wnt/异三聚体 G 蛋白/PI3K 途径用于 PCP 调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5334/7659710/e36ecf2adc27/JCB_201912071_Fig1.jpg

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