EXPRESSION OF AN FSH ANALOG WITH A REROUTED SECRETION PATTERN IN TRANSGENIC MICE

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The human pituitary hormones lutropin (LH) and follitropin (FSH) are part of a family of glycoprotein heterodimers comprised of a common 1 subunit and a hormone-specific [unreadable] subunit. It is the [unreadable] subunit that determines the biological specificity of each hormone. A critical feature of these proteins is their unique secretory patterns. LH is released through a regulated pathway, i.e., it is released by secretagogue, whereas FSH is primarily secreted constitutively. These routings are essential for the coordinated roles of LH and FSH in reproduction. Identifying the determinants that account for the sorting and trafficking of LH and FSH has been a major focus of my laboratory. Using transfected pituitary somatotrope-derived GH3 cells, a novel sequence at the carboxyl end of the LH[unreadable] subunit directing LH to the regulated pathway was identified. Moreover, a chimera comprised of the FSH[unreadable] subunit and this peptide was diverted to the regulated pathway. The primary objective of this R03 pilot proposal is to test the hypothesis that this FSH analog can be rerouted to the regulated pathway in pituitaries of transgenic mice. Thus, what are the physiological consequences of directing FSH from its normal constitutive secretion to the regulated pathway? These experiments will employ FSH[unreadable] knock-out mice using either the human FSH[unreadable] wild type or the human FSH[unreadable] analog transgenes. The advantage of this model is that the sorting and function can be examined in transgenic mice without the background of endogenous mouse FSH. We will examine the secretion from excised pituitaries and potential physiological consequences for the transgenic mice secreting FSH through the regulated pathway. The ability to reroute the pituitary gonadotropins in vivo represents a potentially important model for gonadal dysfunction and provides a novel way to examine normal and ultimately pathophysiological events in the human reproductive tract. PUBLIC HEALTH RELEVANCE: The studies proposed here are designed to study the link between the secretion pathways of FSH and LH and hormonal function. The data obtained from our work will aid in understanding the interplay between these hormones and the development of the follicle. In addition, pathologies in which there is hyper- or hypogonadism can likely be attributed to aberrant secretion of FSH and/or LH from the pituitary.