Mammalian reproduction is a complex physiological process involving interactions between diverse factors synthesized in distinct cell types of the hypothalamic-pituitary-gonadal axis. Alterations within this network of interactions may lead to aberrant reproductive function. Follicle stimulating hormone (FSH) and luteinizing hormone (LH), the two trophic hormones synthesized and secreted from the pituitary gonadotrophs, along with gonadal sex steroids are necessary for normal reproductive function. However, it is less clear what roles various TGF-beta family members (e.g., inhibins, activins, Mullerian inhibiting substance, and growth/differentiation factor 9) play in reproductive physiology. In this proposal, we will generate and analyze multiple transgenic lines of mice to specifically test several hypotheses on the roles of activins, inhibins, activin receptor type II, and growth/differentiation factor 9 in fetal and adult pituitary and gonadal function. These studies approach several issues in reproductive physiology by analyzing the function of both pituitary and gonadal peptides in """"""""loss of function"""""""" experiments in vivo. The power of this transgenic in vivo approach for studying reproductive function is obvious in our initial analysis of mice deficient in activin receptor type II (ActRcII) or growth differentiation factor 9. Mice deficient in ActRcII demonstrate male and female fertility defects, and growth differentiation factor 9-deficient mice demonstrate female infertility secondary to a block in folliculogenesis. The studies described in this proposal will elaborate on these novel transgenic models.
The aims of this proposal are as follows: 1) Study the intrapituitary regulation of FSH biosynthesis by activins and inhibins and characterize the intraovarian roles of activins in vivo; 2) Characterize the infertility defects of mice deficient in the oocyte-specific protein growth/differentiation factor 9 (GDF-9) and define the role of GDF-9 in ovarian function; and 3) Produce recombinant GDF-9 and antiGDF-9 antibodies to further evaluate the roles of GDF-9 in folliculogenesis in vitro and in vivo. These studies and the transgenic mice produced in this proposal will be critical for testing hypothesized roles of these various proteins in the reproductive axis, have already led to new and unexpected insights on the functions of these proteins in vivo, may be important models for human conditions, and in the future may be useful in the testing of therapeutic reagents.
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