HIF1 counteracts FOXO1/Bim-associated follicle atresia in mouse ovaries by promoting Bcl-XL expression

In mammalian ovaries, the majorities of developing follicles (up to 95% in human) undergo atresia. A considerable part of follicle atresia is initiated by granulosa cell (GCs) apoptosis. Our previous work identified hypoxia-inducible factor 1 (HIF1) pathway induced by follicle-stimulating hormone as a protective factor against atresia, yet the molecular mechanism of follicles’ “norm” death, and how HIF1 pathway protect follicles has not been fully delineated. We employed a single-follicle, multi-dimensional profiling strategy based on serial sectioning, to dissect the signaling logic underlying physiological follicle fate decisions. HIF1 and forkhead box protein O1 (FOXO1) pathway show complementary activation patterns in GCs of healthy versus atretic mouse follicles. In growing mouse follicles, HIF1 pathway activity is associated with increased reactive oxygen species (ROS)-related signals, likely through enhanced granulosa-cell metabolic activity. Under the physiological conditions, ROS-related signals appear to help maintain HIF1 pathway activity in mouse granulosa cells during follicle growth, and are not by themselves associated with follicle atresia. HIF1 pathway appears to promote Bcl-XL expression, which may counterbalance FOXO1-associated atretic pressure. In mouse ovaries, follicular fate appears to be associated with the dynamic balance between the pro-survival HIF1/Bcl-XL axis and the pro-apoptotic FOXO1/Bim axis.