LSD1 promotes the FSH responsive follicle formation by regulating autophagy and repressing Wt1 in the granulosa cells

Abstract

In a growing follicle, the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication. Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development, the underlying mechanisms require substantial study. According to our study, along with FSH-induced antral follicles (AFs) formation, both lysine-specific demethylase 1 (LSD1) protein levels and autophagy increased simultaneously in granulosa cells (GCs) in a time-dependent manner, we therefore evaluated the importance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs. Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females, accompanied by marked suppression of the autophagy in GCs. On the one hand, depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog (WT1), at both the protein and mRNA levels. WT1 prevented the expression of FSH receptor (Fshr) in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction. On the other hand, depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs. We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

Keywords: Autophagy; Follicle formation; Follicle stimulating hormone; H3K4me2; LSD1; WT1.