GNRH SIGNALING MECHANISMS IN THE PITUITARY GONADOTROPE

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The multiple endocrine cell populations of the anterior pituitary are key participants in the coordination of endocrine function. Defining the relationships and functional integration of the endocrine cells of the anterior pituitary with the neurosecretory cells of the hypothalamus that regulate pituitary function is essential for understanding the complex interplay of widely differing tissues and organ systems regulated by endocrine effectors. The aims of this proposal investigate the mechanism of a novel regulatory pathway utilized by the gonadotrope cells the anterior pituitary that alters both protein synthesis and cellular proliferation in response to stimulation by the neuronal peptide hormone gonadotropin-releasing hormone (GnRH). Recent experiments in a cultured cell model of pituitary gonadotropes, alphaT3 cells, have defined the mechanism by which the GnRH receptor, a G-protein coupled receptor, activates a signal transduction cascade normally utilized by receptor tyrosine kinases such as the receptors for insulin and other growth factors. We have extended these studies to demonstrate that GnRH influences cellular physiology by an additional pathway that directly regulates of mRNA and initiates proliferation by activation of new DNA synthesis. In the first aim we will define the cellular components of the translation signaling pathway and investigate the regulation of this pathway by GnRH stimulation. In the third aim we will develop a unique transgenic mouse model system for detailed analysis of GnRH signaling in the pituitary. The regulation of translation and cell proliferation by GnRH has important implications for the role of this hormone in the development of the gonadotrope cells of the anterior pituitary. These studies will define the direct and significant role that GnRH may have in the normal function pituitary gonadotropes, and provide important insight into the mechanism of hormone action on target receptor-bearing tissues.