Deletion of GDF-9 in the oocyte results in decreased granulosa cell proliferation, abnormal oocyte growth, and failure of follicles to develop past the primary stage [
43], demonstrating the importance of this growth factor in early follicular development. GDF-9 stimulates rat granulosa cell proliferation, cumulus cell expansion, and preantral follicle growth
in vitro [
44]. We have recently demonstrated that GDF-9 down-regulation attenuates both basal and FSH-induced follicular growth
in vitro, while the addition of recombinant GDF-9 enhances basal and FSH-induced follicular growth in rat [
9]. In addition, down-regulation of GDF-9 content increases caspase-3 activation and granulosa cell apoptosis [
9]. GDF-9 was sufficient to suppress ceramide-induced apoptosis in primary granulosa cells from early antral, but not large/preovulatory follicles [
9], suggesting that GDF-9 is an important granulosa cell survival factor during the preantral to early antral transition, but may play a lesser role in follicle survival past antrum formation. GDF-9 also promotes development and survival of human early follicles in organ culture [
45]. There may be considerable crosstalk between GDF-9 and FSH during the preantral-early antral transition, as GDF-9 is required to maintain FSH receptor expression in the preantral follicles [
9], and GDF-9 receptors (BMPRII and ALK-5) are up-regulated by co-treatment of estrogen and FSH [
46]. Although bone morphogenic protein-15 (BMP-15), another oocyte-specific member of the TGF-β superfamily, is also an important regulator of ovarian function [
33], whether its action in granulosa cells is anti-apoptotic during this transitional stage and important in protecting the preantral follicles from undergoing atresia remains unknown.