Revelations of ovarian follicle biology from gene knockout mice.

Autocrine, paracrine and endocrine factors are necessary for normal ovarian folliculogenesis. A number of studies have demonstrated that the pituitary hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH) as well as granulosa cell-derived growth factors such as activins, inhibins, and kit ligand are necessary for follicle development. Recent knockout studies from our laboratory have demonstrated that mice lacking the pituitary proteins FSHbeta and activin receptor type II are infertile due to blocks at the pre-antral and antral follicle stages, respectively. Although the somatic cells of the ovary (the granulosa and theca cells) have long been implicated in ovarian function, only recently have we shown that the oocyte plays an essential role in controlling its own fate by influencing somatic cell functions. Mice lacking the oocyte-secreted growth factor, growth differentiation factor-9 (GDF-9), are infertile due to a block at the one-layer primary follicle stage, leading to secondary defects in thecal cell layer formation, oocyte growth and meiotic competence, and granulosa cell differentiation. Furthermore, using recombinant GDF-9, we demonstrate that GDF-9 also regulates cumulus expansion and expression of several key granulosa cell-specific genes. Thus, GDF-9 functions as an oocyte-secreted growth and differentiation factor during early and late folliculogenesis and at ovulation to regulate several key somatic cell functions essential for female reproduction.