Reproductive development and function are complex processes requiring both extragonadal factors (e.g., FSH and LH) and intragonadal factors (e.g., steroids and peptide growth factors). Female fertility depends on the regulated allocation, growth, and maturation of oocytes, which must be coordinated with granulosa and theca cell proliferation and differentiation within the ovarian follicular unit. During this process, there are several transitions as follows: 1) Recruitment of quiescent primordial follicles to primary (one layer) follicles by an unknown mechanism; 2) Growth of the granulosa cells of the primary follicle to form two-layered and multi-layered secondary follicles; 3) Formation of antral follicles and further growth of the cells, a process which requires FSH; and 4) Transition of the antral follicle to a preovulatory follicle, in which mural granulosa cells and cumulus granulosa cells take on unique functions, a process induced by LH. Our currently funded competitive renewal (1996-present) hypothesized that the transforming growth factor p superfamily member, growth differentiation factor-9 (GDF-9), is a key oocyte-secreted factor required for transitions 2 and 4. GDF-9 mRNA and protein are specifically expressed within the oocyte beginning at the type 3a primary follicle stage and expressed through ovulation. Using GDF-9 knockout mice and recombinant mouse GDF-9, we have confirmed the above hypothesis. GDF-9 knockout mice are infertile due to a block in folliculogenesis at the primary follicle stage, and recombinant GDF-9 can substitute for the oocyte to regulate genes which are spatiotemporally expressed in the preovulatory ovarian follicle. Thus, GDF-9 is the first oocyte-secreted growth factor identified which plays multifunctional roles in the regulation of ovarian somatic cell function and gene expression. The studies described in this competitive renewal proposal will continue to use these key reagents (i.e., the GDF-9 knockout mice and recombinant GDF-9) and generate additional transgenic mouse models and reagents to further define the functions of GDF-9 and other essential regulators in granulosa cell and theca cell growth and differentiation.
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