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The Role of Smad 3 Signaling
Pathway in the Ovary
Dragana Tomic, M.D.
School of Medicine, University of Maryland, Baltimore
Recently the Smad family of proteins has been shown to mediate the transforming growth factor beta (TGF-²)signaling pathway through the cascade of ligand-induced phosphorylation. The Smads are a family of nine related proteins which can be divided into three different groups: the receptor regulated Smads (Smad 1, 2, 3, 5, 8, and 9), the common-partner Smads (Smad 4) and the inhibitory Smads (Smad 6 and 7). Although the Smad 3 is known to serve as a signaling intermediate for the TGF-²; family in non-reproductive tissues, its role in the ovary is unknown. Our previous research indicates that Smad 3 deficient (Smad 3-/-) female mice have reduced fertility compared to wild-type (WT) mice. This reduced fertility is likely due to slowed follicular growth (i.e. follicles remain in the primordial stage instead of progressing to the antral stage) and increased atresia of antral follicles in Smad 3-/- mice. The mechanism by which a deletion in Smad 3 causes slowed growth of primordial follicles to the antral stage and/or increased atresia of antral follicles is unknown. Thus, the overall goal of this research is to test the hypothesis that deletion of Smad 3 results in slow follicular growth, increased atresia, and infertility by either affecting selected hormone levels, by altering the expression of selected receptors in the ovary and/or by altering genes that regulate cell survival in the ovary. To test this hypothesis, the following specific aims will be completed: 1) evaluate whether the phenotype observed in the Smad 3 deficient animals is due to altered levels of hormones that control follicular development and fertility (follicle-stimulating hormone (FSH), estradiol activin, and inhibin), 2) determine whether Smad 3 signaling pathway alters expression of FSH receptor in the ovary, and 3) evaluate if the Smad 3 signaling pathway alters expression of genes known as bcl-2 family of proto-oncogens. A better understanding of Smad 3 and its regulation in the ovary may lead to development of novel contraceptive methods for women. For example, if we find that Smad 3 directly affects follicular growth in the ovary, one could design compounds that selectively inhibit Smad 3 and thus slow follicular growth to reduce fertility. If we find that Smad 3 causes infertility via changes in the expression of cell death genes, it may be possible to develop compounds that block or stimulate these downstream targets.
