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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Lamar, Charisee A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Salk Institute for Biological Studies
La Jolla
United States
Zip Code
Elbaz, Michal; Hadas, Ron; Bilezikjian, Louise M et al. (2018) Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium. Reprod Biol Endocrinol 16:12
Bilezikjian, Louise M; Justice, Nicholas J; Blackler, Alissa N et al. (2012) Cell-type specific modulation of pituitary cells by activin, inhibin and follistatin. Mol Cell Endocrinol 359:43-52
Bilezikjian, Louise M; Vale, Wylie W (2011) The Local Control of the Pituitary by Activin Signaling and Modulation. Open Neuroendocrinol J 4:90-101
Justice, Nicholas J; Blount, Amy L; Pelosi, Emanuele et al. (2011) Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals. Mol Endocrinol 25:1404-15
Blount, Amy L; Schmidt, Karsten; Justice, Nicholas J et al. (2009) FoxL2 and Smad3 coordinately regulate follistatin gene transcription. J Biol Chem 284:7631-45
Blount, Amy L; Vaughan, Joan M; Vale, Wylie W et al. (2008) A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene. J Biol Chem 283:7016-26
Bilezikjian, Louise M; Blount, Amy L; Donaldson, Cindy J et al. (2006) Pituitary actions of ligands of the TGF-beta family: activins and inhibins. Reproduction 132:207-15