Horomone Control of Gene Expression in the Gonadotrope

调节垂体促性腺激素细胞产生促性腺激素的激素影响的微妙平衡包括激活素和卵泡素(来自性腺和促性腺激素本身)、下丘脑释放激素的脉动模式、促性腺激素释放激素和性腺类固醇激素反馈。在研究项目I中，我们的重点将是激活素、促性腺激素释放激素和类固醇激素调节促性腺激素中黄体生成素和卵泡刺激素β亚基基因表达的细胞和分子机制。我们的模型系统是小鼠，这是因为可以通过基因技术轻松地操纵基因组，并能够利用我们的永生小鼠促性腺激素细胞系来表达FSH、LH、激活素、卵泡素和受体。 用于促性腺激素释放激素、激活素、雄激素、糖皮质激素和孕激素。在特定的目标1中，我们将集中于激活素对FSH和LHβ亚基基因的诱导，以及激活素信号在体内Smad缺陷小鼠促性腺激素中的生理作用。在特定的目标2中，我们将研究促黄体生成素和卵泡刺激素β亚基基因紧张性和脉动性调节的分子机制，并研究促性腺激素释放激素的作用依赖于培养中的激活素自分泌环。在特定的目标3中，我们将讨论类固醇激素信号在FSHβ亚单位基因调节中的作用，培养的重点是雄激素、糖皮质激素和孕激素。与GnRH的情况一样，类固醇激素对FSHβ亚基基因的诱导依赖于促性腺激素中激活素的自分泌，并与激活素的诱导协同作用。我们将在分子水平上研究这种相互作用的基础。最后，我们将利用定向干扰小鼠促性腺激素中的类固醇受体基因来评估这些因素的作用。 活体脑下垂体中的受体。我们的总体目标是解决激活素、促性腺激素释放激素和类固醇激素信号在调节促性腺激素中的促黄体生成素和卵泡刺激素方面的整合。因此，将利用分子、细胞、遗传和小鼠技术来研究多肽激素、生长因子、类固醇、受体和下丘脑释放因子在控制促性腺激素基因表达方面的相互作用，目的是在脑垂体水平上详细了解调节生殖功能的分子机制。

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 gonadal steroid hormone feedback. In Research Project I, our focus will be the cellular and molecular mechanisms of activin, GnRH, and steroid hormone regulation of LH and FSH beta-subunit gene expression in the gonadotrope. Our model system is the mouse, due to the facile manipulations of the genome attainable by genetic technology and the ability to exploit our immortal mouse gonadotrope cell lines that express FSH, LH, activin, follistatin, and the receptors for GnRH, activin, androgens, glucocorticoids, and progestins. In Specific Aim 1, we will focus on the induction of the FSH and LH beta-subunit genes 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 mechanism for tonic and pulsatile regulation of the LH and FSH beta-subunit genes 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 in culture focusing on androgens, glucocorticoids, and progestins. As is the case for GnRH, 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 LH and 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.