Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns cell polarity along the tissue plane and drives polarized cell behaviors during tissue morphogenesis. Accumulating evidence indicates that the vertebrate PCP pathway is regulated by noncanonical, β-catenin-independent Wnt signaling; however, the signaling components and mechanisms are incompletely understood. In the mouse hearing organ, both PCP and noncanonical Wnt (ncWnt) signaling are required in the developing auditory sensory epithelium to control cochlear duct elongation and planar polarity of resident sensory hair cells (HCs), including the shape and orientation of the stereociliary hair bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K pathway that coordinates HC planar polarity and intercellular PCP signaling. Here, we identify Wnt7b as a ncWnt ligand acting in concert with Wnt5a to promote tissue elongation in diverse developmental processes. In the cochlea, Wnt5a and Wnt7b are redundantly required for cochlear duct coiling and elongation, HC planar polarity, and asymmetric localization of core PCP proteins Fzd6 and Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple, a nonreceptor guanine nucleotide exchange factor for Gαi, and activates PI3K/AKT and ERK signaling, which promote asymmetric Fzd6 localization. Thus, ncWnt and PCP signaling pathways have distinct mutant phenotypes and signaling components, suggesting that they act as separate, parallel pathways with nonoverlapping functions in cochlear morphogenesis. NcWnt signaling drives tissue elongation and reinforces intercellular PCP signaling by regulating the trafficking of PCP-specific Frizzled receptors.

中文翻译：

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Wnt7b 与 Wnt5a 协同作用，通过非经典 Wnt 信号传导调节组织伸长和平面细胞极性


由进化上保守的平面细胞极性（PCP）蛋白介导的细胞间信号传导沿着组织平面排列细胞极性，并在组织形态发生过程中驱动极化细胞行为。越来越多的证据表明，脊椎动物的 PCP 通路受到非经典的、不依赖于 β-连环蛋白的 Wnt 信号传导的调节；然而，信号传导成分和机制尚不完全清楚。在小鼠听觉器官中，发育中的听觉感觉上皮需要 PCP 和非经典 Wnt (ncWnt) 信号传导来控制耳蜗管伸长和驻留感觉毛细胞 (HC) 的平面极性，包括静纤毛毛束的形状和方向对于声音检测至关重要。我们最近发现了协调 HC 平面极性和细胞间 PCP 信号传导的 Wnt/G 蛋白/PI3K 通路。在这里，我们将 Wnt7b 确定为 ncWnt 配体，与 Wnt5a 协同作用，在不同的发育过程中促进组织伸长。在耳蜗中，Wnt5a 和 Wnt7b 对于耳蜗管卷曲和伸长、HC 平面极性以及核心 PCP 蛋白 Fzd6 和 Dvl2 的不对称定位是多余的。从机制上讲，Wnt5a/Wnt7b 介导的 ncWnt 信号传导促进 Daple（Gαi 的非受体鸟嘌呤核苷酸交换因子）的膜募集，并激活 PI3K/AKT 和 ERK 信号传导，从而促进不对称 Fzd6 定位。因此，ncWnt 和 PCP 信号通路具有不同的突变表型和信号成分，表明它们在耳蜗形态发生中作为独立、平行的通路，具有不重叠的功能。 NcWnt 信号传导通过调节 PCP 特异性卷曲受体的运输来驱动组织伸长并增强细胞间 PCP 信号传导。