Wnt5a Regulates Junctional Function of Sertoli cells Through PCP-mediated Effects on mTORC1 and mTORC2
Wnt5a Regulates Junctional Function of Sertoli cells Through PCP-mediated Effects on mTORC1 and mTORC2
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Wnt5a 通过 PCP 介导的 mTORC1 和 mTORC2 效应调节支持细胞的连接功能
DOI：
10.1210/endocr/bqab149
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发表时间：
2021-08-02
期刊：
影响因子：
4.8
通讯作者：
Wei, Guanghui
中科院分区：
文献类型：
--
作者：
Fu, Yan;Wei, Yuexin;Wei, Guanghui
血-睾丸屏障(BTB)和顶端胞质特化(ES)是精子发生和精子释放所必需的，它们通过Sertoli细胞和Sertoli生殖细胞的串扰而同步。在这里，我们发现Wnt5a，一个非规范的Wnt信号通路配体，主要在BTB和顶端ES中表达，并且在生精上皮周期中有特定的表达模式。我们利用siRNA在睾丸和Sertoli细胞中敲除Wnt5a的表达，然后鉴定出失去极性并嵌入生精上皮的细长精子细胞。此外，在小管腔附近可见吞噬小体。这些缺陷是由于BTB和心尖ES断裂所致。我们还证实了BTB相关蛋白、肌动蛋白结合蛋白(ABPs)和F-肌动蛋白在体内和体外的表达水平和/或位置在Wnt5a被敲除后发生了变化。此外，我们还证明了Wnt5a通过Ror2介导的mTORC1和mTORC2来调节肌动蛋白的动态。本研究通过平面细胞极性(PCP)信号通路阐明Wnt5a在Sertoli细胞连接中的分子机制。本研究结果可为临床诊断和治疗支持细胞连接损伤引起的男性不育提供实验依据。
The blood-testis barrier (BTB) and apical ectoplasmic specialization (ES), which are synchronized through the crosstalk of Sertoli cells and Sertoli germ cells, are required for spermatogenesis and sperm release. Here, we show that Wnt5a, a noncanonical Wnt signaling pathway ligand, is predominately expressed in both the BTB and apical ES and has a specific expression pattern during the seminiferous epithelium cycle. We employed siRNA to knockdown Wnt5a expression in testis and Sertoli cells, and then identified elongated spermatids that lost their polarity and were embedded in the seminiferous epithelium. Moreover, phagosomes were found near the tubule lumen. These defects were due to BTB and apical ES disruption. We also verified that the expression level and/or location of BTB-associated proteins, actin binding proteins (ABPs), and F-actin was changed after Wnt5a knockdown in vivo and in vitro. Additionally, we demonstrated that Wnt5a regulated actin dynamics through Ror2-mediated mTORC1 and mTORC2. This study clarified the molecular mechanism of Wnt5a in Sertoli cell junctions through the planar cell polarity (PCP) signaling pathway. Our findings could provide an experimental basis for the clinical diagnosis and treatment of male infertility caused by Sertoli cell junction impairment.