REPRODUCTIVE PHYSIOLOGY OF GONADOTROPIN SYNTHESIS

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DESCRIPTION (provided by applicant): The hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH), is the key neuroendocrine regulator of mammalian reproductive development and function. GnRH binds to its target, the GnRH receptor (GnRHR), on pituitary gonadotropes to affect the synthesis and intermittent release of the gonadotropins, luteiriizing hormone (LH) and follicle-stimulating hormone (FSH). Thus GnRH, via the GnRHR, plays a pivotal role in the coordination of reproductive events. Levels of GnRHR in the gonadotrope are tightly regulated and the responses of gonadotropes to GnRH correlate directly with the concentration of GnRHR on the cell surface. Several hormones, most notably GnRH itself and estrogen are critical regulators of transcriptional activation of the GnRHR gene. The overall goal of this application is to understand in detail both the molecular mechanisms and physiological consequences of this hormonal regulation of the GnRHR gene in vitro and in vivo. We have recently identified and characterized several c/s-elements, and their cognate DMA-binding trans-factors, involved in gonadotrope-specific and regulated GnRHR gene expression in vitro. The objectives of this application are: (1) to understand the molecular mechanisms by which these factors integrate signals to dictate GnRHR expression levels; and (2) to characterize the roles of these factors in the regulation of GnRHR gene transcription in vivo. The Specific Aims are: (1) To further define the roles of Pitx-1 and AP-1 (Jun/Fos) proteins in gonadotrope-specific and GnRH-stimulated expression of the mouse GnRHR (mGnRHR) gene; (2) To fully identify the trans-factors that bind to SURG-1, a novel cis-element which we have identified to be necessary for the optimal response of the GnRHR gene to GnRH, and to define their contributions to GnRH responsiveness; (3) To determine the mechanisms of regulation of mGnRHR gene expression by estrogen; and (4) To determine the contributions of the SURG-1 and SURG-2 (AP-1) elements to mGnRHR gene expression and hormonal regulation in vivo using a "knock-in" mouse model. Inasmuch as the GnRHR represents the site that ultimately receives and mediates gonadotrope responses to GnRH, an understanding of the mechanisms of regulation of GnRHR expression is important to our knowledge of mammalian reproductive physiology in both health and disease, and may identify new targets for therapeutic intervention.