Folliculogenesis is a dynamic and progressive process that begins with the initiation of development in primordial follicles and culminates in ovulation of healthy oocytes from follicles that transform into corpora lutea. Information exchanged between the oocyte (OO) and its surrounding somatic follicle cells coordinates folliculogenesis with the process of oogenesis. The central hypothesis being tested in this proposal is that GDF-9 and FSH exert antagonistic influences on an epithelial to mesenchymal transition (EMT) in granulosa cells (GCs).
Three specific aims will be undertaken:(1) To study the regulation of follicle development by GDF-9 in vivo and in vitro. The endogenous distribution of GDF-9 will be determined in normal developing follicles and the hypothesis that GDF-9 modulates granulosa cell proliferation and differentiation will be tested by (1) culturing null phenotype follicles with recombinant GDF-9 or (2) coculturing null phenotype follicles with recombinant GDF-9 impregnated beads, wild-type (WT) follicles, or denuded oocytes. The spatiotemporal influence of GDF-9 on GC polarity, cell cycle state and differentiation will be determined at mRNA and protein levels with respect to maintenance of an epithelial phenotype.(2) To characterize the phenotypic response of granulosa cells to FSH that leads to antrum formation and the ontogeny of mural and cumulus lineages. The hypothesis that FSH modulates cell-cell and cellmatrix interactions and mesenchymal fate will be tested in GC from FSH-beta-deficient animals responding to FSH under in vivo or in vitro conditions, mRNA, protein expression and localization studies of cadherins, beta-catenin, connexins, and integrins will be determined with respect to oocyte, granulosa and basement membrane influences or granulosa cell phenotype.(3) To elucidate the importance of granulosa cell polarity and contact with the oocyte in establishing the epithelial-mesenchymal transition of granulosa. GCs isolated from WT pre-antral/antral or GDF-9, Cx37, or FSH-beta null animals will be analyzed in OO/GC co-culture or follicle culture to ascertain GC cell cycle status prior to or following ligand stimulation. These studies will define the basis for cell cycle regulation at critical stages of follicle development.This work will shed light on the paracrine and hormonal mechanisms deployed within ovarian follicles to coordinate the processes of oogenesis and folliculogenesis. This knowledge will be useful in designing new contraceptive strategies for timely interruption of oocyte development and should enhance the potential utility of in vitro follicle systems for human finical applications in ARTs.
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