Regulation of Follicular Atresia by WIP1-Mediated Apoptosis and Autophagy

Abstract

Female endocrine homeostasis and reproductive success depend on the number and quality of follicles. The follicle is the basic functional unit within mammalian ovaries. Excessive follicular atresia is responsible for the accelerated ovarian aging process. Therefore, exploring the molecular mechanism of follicle development and atresia is essential for protecting ovarian function. In this study, we interrogate the striking correlation between follicular atresia and wild-type p53-induced phosphatase 1 (WIP1) expression in mouse ovaries to understand how WIP1 phosphatase activity regulates follicle development. WIP1 is mainly expressed in granulosa cells of healthy growing follicles, and atretic follicles exhibit significantly weaker WIP1 expression compared with the healthy ones. Our in vivo study indicates that inhibition of WIP1 phosphatase activity causes endocrine disorder, fertility decline and decreased ovarian reserve by triggering excessive follicular atresia through promoting autophagy and apoptosis. By in vitro follicle culture, we determine that inhibiting the WIP1 activity impairs the follicle development, causing more follicular atresia and decreased oocyte quality. Besides, downregulating WIP1 expression in granulosa cells in vitro also promotes apoptosis and autophagy via WIP1-p53 and WIP1-mTOR signal pathway. Our findings from the in vitro and in vivo experiments revealed that appropriate Wip1 expression is required for follicle development. Downregulation of WIP1 expression accelerates follicle atresia via WIP1-p53 and WIP1-mTOR signal pathway related apoptosis and autophagy. It is speculated that moderate up-regulation of WIP1 expression may help delaying the decline of ovarian reserve.