The Center for Reproductive Biological Research

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DESCRIPTION (provided by applicant): Interactions between developing gametes and their neighboring somatic cells are essential for normal fertility. Studies over the last decade established that bidirectional communication between the oocyte and companion granulosa cells is essential for folliculogenesis and development of an egg competent to undergo fertilization and embryogenesis. The Matzuk laboratory and others delineated roles for oocyte-secreted factors such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in the regulation of folliculogenesis in mammals. In the process, the Matzuk laboratory produced key reagents (i.e., recombinant mouse GDF9, monoclonal antibodies that detect mouse GDF9 by immunohistochemistry and Gdf9 and Gdf9/Bmp15 knockout mice that are infertile) that were useful for the above studies and helped to identify cumulus granulosa cell genes that are directly regulated by GDF9. Recent evidence supports the presence of GDF9 and BMP 15 mRNA and protein in the ovary of primates, and the downregulation of GDF9 mRNA in women with polycystic ovarian syndrome. However, little is known about the significance of GDF9 and BMP 15 in oocyte-somatic cell communication during follicular development in primates or in human diseases. An important role for GDF9 and/or BMP15 can be implied from the recent data of Dr. Matzuk and colleagues that levels of expression of GDF9-regulated cumulus cell genes correlate with subsequent embryo development during assisted reproductive protocols in infertile women. The following translational study was designed to: 1) develop important GDF9 and BMP 15 related reagents; and 2) begin investigations to unravel the functions of GDF9 and BMP15 in oocyte-granulosa cell interactions during preovulatory follicular development in primates. The Specific Aims of the proposed U54 collaborative research initiative are as follows: 1) Produce large amounts of purified recombinant human GDF9 and BMP15 and anti-GDF9 and anti-BMP 15 neutralizing antibodies for in vitro and in vivo studies; and 2) Use bioactive GDF9 and BMP15 and anti-human GDF9/BMP15 antibodies for comparative analysis of gene expression and functional assays in mouse, nonhuman primate, and human pre-ovulatory granulosa cells/cumulus cell-oocyte complex systems. The current collaboration between Drs. Martin M. Matzuk and Richard L. Stouffer should yield important and clinically relevant findings for understanding human ovarian function, fertility, and reproductive diseases.