Reproductive Biology of Gonadotropin Regulation

促性腺激素、黄体生成素(LH)和卵泡刺激素(FSH)在生殖轴中起着不可或缺的作用。将神经和荷尔蒙的输入转化为精确调节的输出，以实现正常性发育和性腺功能的调节。该项目的长期目标是阐明促性腺激素基因表达调控的分子机制，这将为了解正常和异常生殖功能提供信息。近年来，对组织特异性和促性腺激素释放激素刺激的LHbeta基因表达的分子机制的研究取得了长足的进展。然而，人们对FSHbeta基因的转录调控机制知之甚少。本研究的目的是以新近建立的LbetaT2细胞系和转基因小鼠为模型，探讨大鼠FSHbeta基因在体外和体内的组织特异性和激素调控表达的机制。在第一个目标中，我们将检验我们的假设，即同源结构域蛋白Pitx1直接与FSHbeta启动子中的特定元件结合，并与其他转录因子相互作用，协同激活促性腺激素特异性和激素调节的FSHbeta基因转录。其次，我们将基于SF-1和DAX-1对FSHbeta和LHbeta基因有不同影响的假设，表征两个相互作用的孤儿核受体SF-1和DAX-1在FSHbeta基因表达调控中的作用，这可能是体内FSH和LH的一些不同调控反应的基础。在第三个目标中，我们计划识别和表征介导GnRH调节FSHbeta基因表达的顺式元件和它们的同源反式因子。最后，我们建议表征激活素对FSHβ基因转录刺激的机制，激活素是FSH产生的重要生理调节因子。通过对调节组织特异性和激素调节的FSHbeta基因表达的因素的表征，我们将能够更好地阐明生殖功能障碍的潜在机制，并可能为治疗干预找到新的靶点。

The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play an integral role in the reproductive axis. translating neural and hormonal input into precisely regulated output to achieve normal sexual development and regulation of gonadal function. The long-term objective of this project is to elucidate the molecular mechanisms underlying regulation of gonadotropin gene expression, information that will provide insight into both normal and abnormal reproductive function. In recent years, considerable progress has been made in the elucidation of the molecular mechanisms underlying tissue- specific and GnRH-stimulated expression of LHbeta gene. However, relatively little is known about the mechanisms of transcriptional regulation of the FSHbeta gene. The goal of this proposal is to explore mechanisms of tissue-specific and hormonally-regulated expression of the rat FSHbeta gene in vitro and in vivo, using the recently developed LbetaT2 cell line and transgenic mice as models. In the first aim, we will test our hypothesis that the homeodomain protein Pitx1 binds directly to specific elements in the FSHbeta promoter and interacts with other transcription factors to synergistically activate gonadotrope-specific and hormonally regulated FSHbeta gene transcription. Secondly, we will characterize the roles of the two interacting orphan nuclear receptors, SF-1 and DAX-1, in the regulation of FSHbeta gene expression, based on our hypothesis that SF-1 and DAX-1 have distinct effects on the FSHbeta and LHbeta genes, which may underlie some of the differential regulatory responses of FSH and LH that occur in vivo. In the third aim, we plan to identify and characterize cis-elements, and their cognate trans-factors, which mediate GnRH-regulated expression of the FSHbeta gene. Finally, we propose to characterize the mechanisms of transcriptional stimulation of the FSHbeta gene by activin, an important physiologic regulator of FSH production. By characterizing the factors that mediate tissue-specific and hormonally-regulated FSHbeta gene expression, we will be better able to elucidate the mechanisms underlying disorders of reproductive function, and may identify new targets for therapeutic intervention.