PARACRINE INTERACTIONS IN PROLACTIN SECRETION

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Well-defined distribution of various pituitary cells types in the anterior pituitary (AP) gland suggest that Cell-to-Cell interactions play an important role in the development, function and proliferation of AP cells. Previous studies from this laboratory have shown that calcitonin- like immunoreactive peptide (pit-CT) is synthesized and secreted by cultured AP cells. It may affect lactotrope function because synthetic sCT is a potent inhibitor of PRL secretion and PRL gene transcription. Our recent studies have used immunohistological, cell culture and molecular approaches to demonstrate that putative pit-CT mRNA and pit-CT IR peptide is selectively expressed by gonadotropes and RC4B cells (tumor cells of gonadotropelineage), and not by alphaT-3, GH3 or AT20 cells. Temporally, pit-CT gene expression is initiated subsequent to, and not prior to, the expression of LH Beta-subunits because pit-CT mRNA could not be detected in alphaT-3 cells or fetal AP gland (embryonic day 19), but could be detected in the AP gland of day 20 fetal age. The studies in adult AP glands have shown that pit-CT IR gonadotropes were surrounded by cup-shaped lactotropes, suggesting a role for pit-CT in juxtacrine inhibition of lactotrope function. Physiological significance of pit-CT action was demonstrated by the findings that passive immunization of pit- CT with anti-sCT serum caused a dramatic increase in PRL secretion under in vitro and in vivo conditions. Pit-CT IR content of the AP gland varied significantly in various physiological conditions. Three days of E2 treatment caused a nine-fold decline in putative pit-CT mRNA abundance and also caused four-fold decrease in pit-CT IR concentrations. In contrast, ovariectomy induced a three-fold increase in pit-CT IR content. Thus, pit-CT is a novel, physiologically relevant, gonadotrope-derived inhibitor of lactotrope function. Since we have obtained a putative pit- CT cDNA clone and the expression of putative pit-CT mRNA parallels the expression of pit-CT IR, an objective of the present proposal is to identify the precise role for pit-CT in maturation, function and proliferation of lactotropes during development and adulthood. Specific Aim of the proposal will develop RC4B-lactotrope co-culture model to test the role of endogenous pit-CT in lactotrope function and proliferation. Specific Aim 2 will study the consequence of gonadotrope-depletion or pit-CT overexpression on lactotrope function. Specific Aim 3 and 4 will further characterize the actions of gonadal steroids and other paracrine and neuroendocrine factors on pit-CT expression. These studies will provide new and significant findings towards the role of gonadotrope- lactotrope interactions in pituitary function. These results will make important contributions in understanding physiology of normal reproduction and pathophysiology of aging.