Mammalian reproduction is a complex process requiring the interaction of multiple factors at the levels of hypothalamus, pituitary, and ovaries and testes. The rapid advances in embryonic stem (ES) cell and transgenic mouse technology have allowed investigators to address the essential functions of several of these factors in vivo. To understand ovarian function, we have created important transgenic mouse models deficient in growth differentiation factor 9 (GDF-9), follicle stimulating hormone (FSH), activin receptor type II (ActRII), and germ cell nuclear factor (GCNF). Female mice deficient in GDF-9, FSH, and ActRII are infertile due to blacks at specific stages of folliculogenesis. In contrast, GCNF- deficient mice die at mid-gestation due to important role of GCNF during extraembryonic development of the placenta. GCNF is an orphan member of the nuclear receptor superfamily expressed in the developing germ cells of the adult mouse. In the oocyte, GCNF is expressed from the one layer primary follicle stage through ovulation similar to the TGF-beta family member, GDF-9. In addition, we have recently identified another TGF-beta family member, Novel 1, which has a pattern of oocyte-specific expression similar to GDF-9 and GCNF. To characterize the functions of GCNF and Novel 1 during ovarian development, we will generate several new transgenic mouse lines.
The Specific Aims of these studies are as follows: 1) Characterize the role of Novel 1 in mouse ovarian development; 2) Study the physiological function of GCNF in oocyte maturation; 3) Analyze the regulation of GCNF and Novel 1 in mouse and human oocytes and germ cell tumors; and 4) Use transgenic mice with multiple defects and mRNA expression analysis to define the interrelated roles of several gene products in ovarian development and function. The above-mentioned studies will assess the important roles of these genes in ovarian development. We hypothesize that Novel 1-deficient mice and mice with an ovary-specific knockout of GCNF will be infertile secondary to early blocks in folliculogenesis. If this hypothesis is true and these mutant female mice exhibit fertility defects, GCNF and Novel 1 may be potential targets for new contraceptive agents and treatment of human infertility.
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