The Role of Fibroblast Growth Factor-18 in Follicular Atresia in Cattle

Although the various members of the fibroblast growth factor (FGF) family are generally mitotic, one member, FGF18, has been shown to increase the rate of apoptosis of ovarian granulosa cells. In the present study, we first determined whether granulosa cells express FGF18 and we then explored the mechanism through which FGF18 increases apoptosis in vitro. Under culture conditions that favored estradiol secretion and CYP19A1 expression, granulosa FGF18 mRNA levels were barely detectable; however, withdrawing gonadotropic support (follicle-stimulating hormone or insulin-like growth factor 1) reduced levels of CYP19A1 mRNA and increased abundance of mRNA encoding the death ligand FASLG and FGF18. Addition of FGF18, but not FGF2, FGF10, or EGF, increased the proportion of apoptotic cells and frequency of caspase 3 activation, and these effects were abrogated by coculture with estradiol. Addition of FGF18 decreased abundance of mRNA encoding the antiapoptotic proteins GADD45B and MDM2, and increased that encoding the proapoptotic protein BBC3; these effects were reversed by coculture with estradiol. The physiological relevance of FGF18 was determined using an in vivo model: injection of FGF18 directly into growing bovine dominant follicles caused cessation of follicle growth by 24 h after injection. Collectively, these data demonstrate that FGF18 is proapoptotic in vivo and may act through a mechanism involving the BBC3-MDM2 pathway.