The Inhibition of WIP1 Phosphatase Accelerates the Depletion of Primordial Follicles

Abstract Research Question : The aim of the present study is to elucidate the role of wild-type p53-induced phosphatase 1 (WIP1) in regulating primordial follicle development. Design WIP1 expression was detected in the ovaries of mice of different ages by western blotting and immunohistochemical staining. Three-day-old neonatal mouse ovaries were cultured in vitro with or without the WIP1 inhibitor GSK2830371 (10 μM) for 4 days. We analyzed the ovary morphology, follicle growth, and follicle classification, and evaluated the PI3K–AKT–mTOR signal pathway and the WIP1–p53-related mitochondrial apoptosis pathway. Results : WIP1 expression was downregulated with age. Primordial follicles were significantly decreased in the GSK2830371-treated group, without a significant increase in growing follicles. The ratio of growing follicles to primordial follicles was not significantly different between the control and GSK2830371 groups, and there was no significant variation in the PI3K–AKT–mTOR signal pathway. The inhibition of WIP1 phosphatase accelerated primordial follicle atresia by activating the p53–BAX–caspase-3 pathway. Conclusions : These findings reveal that WIP1 participates in regulating primordial follicle development and that inhibiting WIP1 phosphatase leads to massive primordial follicle loss via interaction with the p53–BAX–caspase-3 pathway, which might also provide valuable information for understanding decreased ovarian reserve during ovarian aging.