The major objective of this research proposal is to gain an understanding of how activin-dependent Smad signaling leads to follistatin gene activation in anterior pituitary gonadotropes. Activins are widely expressed pleiotropic regulators of diverse tissues and cellular functions, including the differential production of FSH from gonadotropes of the anterior pituitary. Thus of necessity, the actions of activins are under the precise control of multiple mechanisms of functional inactivation or antagonism. Follistatins are secreted activin-binding glycoproteins that function extracellularly to modulate the bio-availability of activins in most tissues. Although first identified as FSH-suppressing components of gonadal fluids, numerous studies have since documented the presence of follistatin in many tissues, including gonadotropes and other cell types of the anterior pituitary. Activins are one of the most potent inducers of follistatin expression and it is now presumed that many of the demonstrated actions of follistatins reflect their local autocrine/paracrine influence on the bioactivity of activins and possibly other TGF-Beta family members. As testimony to the importance of their actions to counterbalance the diverse effects of activins, mice null for follistatin exhibit many embryonic defects and die shortly after birth. On the other hand, follistatin over-expression is associated with infertility because of functional disruptions at the level of the gonads and the pituitary. In the anterior pituitary, the inducible expression of follistatin establishes a feedback loop and a mechanism for activin to self-modulate further signaling. The focus of this proposal is to elucidate the poorly understood mechanism underlying the regulation of follistatin gene expression in gonadotropes. We have obtained strong evidence that elements in the fin'st intron of the rat follistatin gene mediate the transcriptional effects of activin, via Smad signaling, on this gene in gonadotrope-derived alphaT3-1 and LBetaT2 cells. We propose to use complementary approaches to define precisely the elements of the activin-responsive region located in the first intron of the rat follistatin gene, to characterize gonadotrope-derived factor(s) that mediate these effects of activin in conjunction with Smad3 and Smad4 and, finally, to determine the function of these factors as obligate mediators of this action of activin. The proposed studies also aim to determine if activin induces follistatin expression by the same mechanism in other pituitary and non-pituitary cell types. Altogether, these studies will provide important insights into the mechanism by which activin controls follistatin expression in gonadotropes and identify selective therapeutic targets for the management of reproductive and other endocrine disorders.
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