SELECTION OF THE DOMINANT FOLLICLE AND THE IGF SYSTEM

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What regulates the selection, from among a cohort, of a species-specific number of follicles for ovulation is one of the most important unanswered questions in mammalian ovarian biology. This proposal is focused on the potential role of the insulin-like growth factor (IGF) system in selection of follicles for dominance and potential ovulation. Cattle are an ideal model for such studies because ultrasound imaging has elucidated the regular patterns of follicular recruitment, selection, and dominance that occur at predictable intervals and can be manipulated experimentally. IGF is known to synergize with FSH to promote follicular growth and differentiation. In contrast, IGF binding proteins (IGFBPs) bind IGF and inhibit its actions within the follicle. IGFBP proteases release IGF from its BPs and allow it to act on follicular cells. Our preliminary data indicate that inhibitory IGFBPs are lower in dominant than in subordinate follicles and that dominant follicles acquire a protease for at least one of the IGFBPs (IGFBP-4) around the time of follicular selection for dominance. Therefore, the overall hypothesis of this proposal is that the ovarian IGF system plays a critical role in the selection of the dominant follicle in cattle. This hypothesis will be tested first by determining the relative levels of inhibitory IGFBPs (BP-4 and BP-2) and their putative proteases in follicular fluid and relative levels of IGFBPs and their mRNAs in follicular tissue from follicles obtained before, during and after follicular selection (Specific Aims 1 and 2). In Specific Aim 3 an experimental model for producing co-dominant follicles will be used to further test the postulated association between dominance and specific changes in IGFBPs and their proteases. Since waves of follicular development are believed to be initiated by small increases in plasma FSH, Specific Aim 4 is to determine the effects of gonadotropins on the secretion of IGFBPs and IGFBP protease activity by theca and granulosa cells isolated from follicles at specific times during follicular selection and cultured in vitro. Specific Aim 5 is to establish a causal link between changes in IGFBPs and their proteases and selection of the dominant follicle by determining if specific IGFBPs inhibit gonadotropin and/or IGF-I-induced steroid secretion by granulosa and theca cells in vitro.