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Autophagy regulates differentiation of ovarian granulosa cells through degradation of WT1

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journal contribution
posted on 13.01.2022, 19:20 by Tong Shao, Hanni Ke, Ran Liu, Lan Xu, Shuang Han, Xiruo Zhang, Yujie Dang, Xue Jiao, Wei Li, Zi-Jiang Chen, Yingying Qin, Shidou Zhao

Ovarian granulosa cells (GCs) proliferate and differentiate along with follicular growth, and this is indispensable for oocyte development and female fertility. Although the role of macroautophagy/autophagy in ovarian function has been reported, its contribution to the regulation of GC characteristics remains elusive. The siRNA-mediated knockdown of two key autophagy-related genes ATG5 and BECN1 and the autophagy inhibitor chloroquine were used to interfere with autophagy in GCs. Inhibition of autophagy both genetically and pharmacologically resulted in decreased expression of genes associated with GC differentiation, including CYP19A1/Aromatase and FSHR, as well as in reduced estradiol synthesis. Mechanistically, when autophagy was disrupted, the transcription factor WT1 accumulated in GCs due to its insufficient degradation by the autophagic pathway, and this inhibited GC differentiation. Finally, decreased expression of several autophagy-related genes, as well as reduced LC3-II:LC3-I and elevated SQSTM1/p62 protein levels, which are indications of decreased autophagy, were detected in GCs from biochemical premature ovarian insufficiency patients. In summary, our study reveals that autophagy regulates the differentiation of ovarian GCs by degrading WT1 and that insufficient autophagy might be involved in ovarian dysfunction.

Funding

This work was supported by the National Key Research & Development Program of China [2018YFC1003800 and 2017YFC1001100], Taishan Scholars Program for Young Experts of Shandong Province [tsqn20161069], National Natural Science Foundation of China [81873823 and 81771541], Basic Science Center Program of NSFC [31988101], Young Scholars Program of Shandong University [2016WLJH26] and The Fundamental Research Funds of Shandong University.

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