Conserved SERPINE2 function maintains ovarian estrogen production to support fertility in goats and mice

Abstract

Abstract Molecular relays bridging extracellular cues and intracellular steroidogenic enzymes in granulosa cells (GCs) during mammalian folliculogenesis remain poorly defined. Single‐nucleus RNA sequencing and functional profiling of goat ovaries with divergent litter sizes revealed prolificacy‐associated GC states characterized by increased proliferation‐associated signatures, higher estradiol (E 2 ) output, and altered predicted cell–cell communication. We identified SERPINE2 as a prolificacy‐associated candidate regulator enriched in GCs, whose expression parallels the aromatase gene CYP19A1 . Exploratory analyses in a successful‐kidding cohort of multiparous Nubian does showed observational associations of postpartum circulating SERPINE2 with serum E 2 and realized litter size. Cross‐species analyses in goat and murine GCs indicated that SERPINE2 supports GC proliferation, survival, and estrogen production. Biochemical and epistasis analyses support a working model in which WNT7B contributes to SERPINE2‐dependent GC responses, whereas CYP19A1 is required for the full steroidogenic response. In vivo, GC‐specific Serpine2 ablation in mice was accompanied by reduced WNT7B and CYP19A1 abundance, impaired androgen‐to‐estrogen conversion, compromised follicular development, and subfertility. Collectively, these findings support a role for SERPINE2 in GC steroidogenic function and a working model involving WNT7B and CYP19A1 in ovarian estrogen production.