Non-Canonical Wnt Signaling Regulates Cochlear Outgrowth and Planar Cell Polarity via Gsk3β Inhibition.
Non-Canonical Wnt Signaling Regulates Cochlear Outgrowth and Planar Cell Polarity via Gsk3β Inhibition.
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DOI：
10.3389/fcell.2021.649830
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发表时间：
2021
影响因子：
5.5
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Landin Malt A;Clancy S;Hwang D;Liu A;Smith C;Smith M;Hatley M;Clemens C;Lu X
在发育过程中，耳蜗感觉毛细胞（HCs）在其顶端表面形成具有平面极化结构和取向的立体纤毛束。我们最近发现了一种非规范的Wnt/ g蛋白/PI3K信号通路，该信号通路促进耳蜗生长，并协调耳蜗顶端细胞骨架的平面极化和耳蜗上皮上的HC取向排列。在这里，我们确定了激酶Gsk3β和小GTPase Rac1参与耳蜗非规范Wnt信号传导及其对平面细胞极性（PCP）通路的调节。我们首次在体内提供了Wnt通过抑制Ser9磷酸化来调节Gsk3β活性的证据。此外，我们还对阻断Wnt分泌导致的耳蜗缺损进行了基因拯救实验。我们发现，基因消融Gsk3β可以部分恢复耳蜗的生长，但稳定的β-catenin的表达却不能；而PCP缺陷，包括毛束极性和核心PCP蛋白Fzd6和Dvl2的连接定位，可以通过Gsk3β消融或Rac1的组成性激活部分修复。我们的研究结果确定Gsk3β和可能的Rac1是非规范Wnt信号的下游组分，也是耳蜗生长、HC平面极性和耳蜗核心PCP蛋白子集定位的介质。
During development, sensory hair cells (HCs) in the cochlea assemble a stereociliary hair bundle on their apical surface with planar polarized structure and orientation. We have recently identified a non-canonical, Wnt/G-protein/PI3K signaling pathway that promotes cochlear outgrowth and coordinates planar polarization of the HC apical cytoskeleton and alignment of HC orientation across the cochlear epithelium. Here, we determined the involvement of the kinase Gsk3β and the small GTPase Rac1 in non-canonical Wnt signaling and its regulation of the planar cell polarity (PCP) pathway in the cochlea. We provided the first in vivo evidence for Wnt regulation of Gsk3β activity via inhibitory Ser9 phosphorylation. Furthermore, we carried out genetic rescue experiments of cochlear defects caused by blocking Wnt secretion. We showed that cochlear outgrowth was partially rescued by genetic ablation of Gsk3β but not by expression of stabilized β-catenin; while PCP defects, including hair bundle polarity and junctional localization of the core PCP proteins Fzd6 and Dvl2, were partially rescued by either Gsk3β ablation or constitutive activation of Rac1. Our results identify Gsk3β and likely Rac1 as downstream components of non-canonical Wnt signaling and mediators of cochlear outgrowth, HC planar polarity, and localization of a subset of core PCP proteins in the cochlea.
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影响因子：
34.7
作者：
Hur, Eun-Mi;Zhou, Feng-Quan
通讯作者：
Zhou, Feng-Quan
DOI：
10.1523/jneurosci.3998-09.2009
发表时间：
2009-12-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Grimsley-Myers CM;Sipe CW;Géléoc GS;Lu X
通讯作者：
Lu X
DOI：
10.1073/pnas.1222341110
发表时间：
2013-08-20
影响因子：
11.1
作者：
Bok, Jinwoong;Zenczak, Colleen;Wu, Doris K.
通讯作者：
Wu, Doris K.
影响因子：
4
作者：
de Curtis, Ivan;Meldolesi, Jacopo
通讯作者：
Meldolesi, Jacopo
DOI：
10.1083/jcb.201912071
发表时间：
2020-10-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Landin Malt A;Hogan AK;Smith CD;Madani MS;Lu X
通讯作者：
Lu X