Stromal Senp1 promotes mouse early folliculogenesis by regulating BMP4 expression

Background: Mammalian folliculogenesis, maturation of the ovarian follicles, require both growth factors derived from oocyte and surrounding cells, including stromal cells. However, the mechanism by which stromal cells and derived factors regulate oocyte development remains unclear. Results: We observed that SENP1, a small ubiquitin-related modifier (SUMO)-specific isopeptidase, was expressed in sm22a-positive stromal cells of mouse ovary. The sm22a-positive stromal cells tightly associated with follicle maturation. By using the sm22a-specific Cre system, we show that mice with a stromal cell-specific deletion of SENP1 exhibit attenuated stroma-follicle association, delayed oocyte growth and follicle maturation with reduced follicle number and size at early oocyte development, leading to premature ovarian failure at late stages of ovulating life. Mechanistic studies suggest that stromal SENP1 deficiency induces down-regulation of BMP4 in stromal cells concomitant with decreased expression of BMP4 receptor BMPR1b and BMPR2 on oocytes. Conclusions: Our data support that protein SUMOylation-regulating enzyme SENP1 plays a critical role in early ovarian follicle development by regulating gene expression of BMP4 in stroma and stroma-oocyte communication.