Hormone and Growth Factor Control of Ovarian Cell Biology

In its broadest context, our research deals with the area of localized tissue growth and differentiation. The model is the ovary during the reproductive cycle. During each reproductive cycle, granulosa cells in the follicle(s) selected for ovulation undergo a dramatic wave of cell replication. Daughter cells emerge with a different complement of hormone receptors and steroidogenic enzymes. This process is entrained to pituitary signals, but restricted to only a few selected follicles of the hundreds in the ovary. The primary hypothesis is that growth factors, secreted locally under hormonal control, mediate the selective growth and differentiation of ovarian follicles chosen for ovulation. The growth factor system of principal interest is the ovarian IGF system. The expression of these peptides in vivo is analyzed during the reproductive cycle using immunochemical techniques, mRNA measurements and in situ hybridization. Such studies have indicated highly selective expression of IGFs, their receptors, and their soluble binding proteins. This expression is also studied in ovarian cell cultures and cell lines developed in our laboratory. One area of current emphasis is regulation of IGF-I transcription by gonadotropic hormones. Our studies have shown that FSH and growth hormone induce a coordinated increase in IGF mRNA and peptide synthesis. Multiple mRNA and peptide precursors have been delineated suggesting several potentially important processing steps. However, the major locus for hormone action is transcriptional. The cis and transacting factors which mediate this response are being determined. A second major area of research is extra cellular "targeting" of IGFs via the IGF binding proteins (IGFBPs). These proteins attach to IGF target cells and bind the IGFs with high affinity. They may direct the action of the growth factors. The nature of the cellular attachment and processing sites for the IGFBPs is being defined by a variety of ligand-binding and crosslinking techniques coupled with site-directed mutagenesis. Finally, the reproductive consequences of IGF system gene disruption or overexpression are being examined in transgenic mice. Initial studies are directed at characterization of ovarian function in mice bearing a null mutation in IGFBP-2. Other informative mutants are being developed.