Reproductive Biology of Gonadotropin Regulation

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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.