Endocrine and Growth Factor Regulation in the Pituitary

University Of California San Diego, La Jolla CA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): The delicate balance of hormonal influences that governs gonadotropin production by the pituitary gonadotrope cell includes activin and follistatin (derived from the gonad and from the gonadotrope itself), the pulsatile pattern of the hypothalamic releasing hormone, GnRH, and steroid hormone feedback. In this revised application, our focus will be on the molecular mechanisms of activin, GnRH, and steroid hormone regulation of FSH beta-subunit gene expression in the gonadotrope. Our overall hypothesis is that activin is critical for appropriate regulation of the FSH beta-subunit gene including full regulation by GnRH and steroid hormones. Our model system is the mouse, due to the facile manipulations of the genome attainable using genetic technology and the ability to exploit our immortalized mouse gonadotrope cell lines that express FSH, LH, activin, follistatin, and the receptors for GnRH, activin, androgens, progestins, and glucocorticoids. In Specific Aim 1, we will focus on the molecular mechanisms of induction of the FSH beta-subunit gene by activin and the physiological role of activin signaling in the gonadotrope in vivo in Smad-deficient mice. In Specific Aim 2, we will investigate the molecular mechanisms for tonic and pulsatile regulation of the FSH beta-subunit gene and study the dependence of GnRH action on the activin autocrine loop in culture. In Specific Aim 3, we will address the roles of steroid hormone signaling in regulation of the FSH beta-subunit gene focusing on androgens, progestins, and glucocorticoids. As is the case for GnRH, full steroid hormone induction of the FSH beta-subunit gene is dependent upon activin autocrine tone in the gonadotrope and synergistic with induction by activin. We will investigate the basis of this interaction at the molecular level. Finally, we will utilize targeted disruption of the steroid receptor genes in the gonadotrope in mice to assess the role of these receptors in the pituitary in vivo. Our overall goal is to address the integration of activin, GnRH, and steroid hormone signaling in the regulation of FSH in the gonadotrope. Thus, the interplay of peptide hormones, growth factors, steroids, receptors, and hypothalamic releasing factors in controlling gonadotropin gene expression will be investigated using the armamentarium of molecular, cellular, genetic, and mouse technologies with the goal of developing a detailed understanding of the molecular mechanisms mediating reproductive function at the level of the pituitary. [unreadable] [unreadable]