GnRH Signaling Mechanisms in the Pituitary Gonadotrope

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DESCRIPTION (provided by applicant): Understanding the development and regulation of the tissues that comprise the reproductive endocrine axis is essential to understanding reproductive function. The central regulatory hormone controlling reproductive function is the neuropeptide gonadotropin-releasing hormone I (GnRH). The principal target of GnRH I is the population of gonadotropes in the anterior pituitary. Pulsatile GnRH stimulation of gonadotropes results in increased synthesis and release of the heterodimeric gonadotropin hormones Luteinizing Hormone and Follicle-Stimulating Hormone into the general circulation. During the previous funding period we described the novel property of translational control by the GnRH receptor. Translational control is a means of direct regulation of gene expression that is uniquely suited to the rapid in vivo changes in GnRH pulse amplitude and frequency. In this renewal application, it is our goal to develop a thorough understanding of GnRH action that accounts for short-term changes in gonadotropin gene expression through alterations in gonadotropin protein synthesis. Our aims are directed toward a basic understanding of the mechanisms of GnRH signaling that mediate translational control in gonadotropes. We will then define the structural basis for the specificity of translation control, and extend our studies to investigate the role of pulsatility in gene regulation. Aim 1: Regulation of translation by GnRH. We will define the targets of GnRH action that mediate translational control in a gonadotrope cell line. We will confirm our findings in primary pituitary culture and in a novel transgenic mouse model. Aim 2: Specificity of mRNA utilization by GnRH. We will determine the sensitivity of gonadotropespecific genes to translational control to establish the specificity of regulation through this mechanism. We will determine the molecular basis for this specificity. Aim 3: Regulation of gonadotropin synthesis by pulsatile GnRH. We hypothesize that translation and transcription are differentially regulated by differing GnRH pulse regimes. We will test this and alternate models of regulation by determination of the degree of regulatory component activation and determination of the role of negative feedback signaling in modulating the response to GnRH stimulation.