The Role of the Hedgehog Signaling Pathway in Ovarian Follicle Development

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DESCRIPTION (provided by applicant): The objective of the proposed research is to determine how signaling through the hedgehog (hh) pathway regulates development in the mammalian ovary. The hh proteins are a family of secreted proteins that direct development in the embryo and in adult tissues, influencing cell fate determination, proliferation, differentiation and patterning of tissues. Mutation-induced increases in hh signaling cause cancer in many of the same tissues in which hh is critical for normal development. Hh signaling is required for ovarian follicle development in Drosophila but its role in the mammalian ovary is not known. There are three mammalian hh proteins, sonic (shh), indian (ihh) and desert (dhh), and each of them signals through the receptor smoothened (smo). Homozygous null mutations of hh pathway components in mice cause embryonic mortality and, consequently, fail to define the role of hh in the ovary. Data in support of this application show that major components of the hh pathway are expressed in the mouse ovary. We have used cre/lox technology to conditionally delete or to activate smo in the mouse ovary in order to determine the role of hh signaling in vivo. This R03 proposal focuses on experiments to characterize a defect in the final stages of follicle development observed in mice in which an altered, dominant active form of smo is expressed in the ovary. It is hypothesized that hh signaling normally promotes the development of follicles as they grow from the primary to the preovulatory stage. The preovulatory LH surge then triggers a decline in hh signaling which is essential to allow the final stages of follicle cell differentiation to occur. This differentiation is necessary for cumulus expansion, ovulation and luteinization. Comparison of mice in which dominant active smo is expressed in the ovary to genotype-matched control mice will identify gene pathways essential for the final stages of preovulatory follicle development and indicate how hh signaling is involved in this process. This R03 pilot project will establish a transgenic mouse model and begin to test mechanistic hypotheses to promote our understanding of the role of hh signaling in ovarian development. Follicle development requires complex signaling, which is often regulated by the hh pathway in other tissues. A thorough understanding of developmental pathways in the ovary is essential to promote development of methods to enhance or control fertility, to determine the causes of disease and to develop treatments. Follicle development requires complex signaling, which is often regulated by the hedgehog signaling pathway in other tissues. A thorough understanding of developmental pathways in the ovary is essential to promote development of methods to enhance or control fertility, to determine the causes of disease and to develop treatments.