The anterior pituitary gonadotrope is a unique endocrine cell which serves as the focal point for integration of hormonal signals in the regulation of the menstrual cycle. It expresses both FSH and LH, it responds to gonadal steroids in the classical feedback loop, to pulses of GnRH from the hypothalamus, and to the interplay of activin, inhibin, and follistatin produced not only in the gonad but in the gonadotrope itself. This remarkable confluence of interacting hormones, growth factors, and receptors within a single cell denotes an intricate set of endocrine and autocrine responses that are differentially modulated to regulate transcription and secretion of FSH and LH, in the delicately fluctuating equilibrium controlling reproductive function. The molecular basis of developmental and hormonal control in the gonadotrope could not be effectively investigated heretofore due to the lack of differentiated cell lines. Methods for targeted oncogenesis in transgenic mice have enabled us to derive immortalized endocrine cell lines from the pituitary. Our success in immortalization of cells representing progenitors for the gonadotrope and somatotrope provides the opportunity to expand this approach to the study of the FSH beta-subunit gene by targeting oncogenesis to a later stage gonadotrope. In Unit 2, we propose to develop an immortal cultured cell line representing a mature anterior pituitary gonadotrope. This cell line and the existing gonadotrope cell lines will be used to investigate the mechanisms of developmental control of the FSH beta gene in pituitary cells and to investigate the molecular basis of hormonal regulation of FSH beta gene expression by steroids, growth factors and releasing hormones. Furthermore, to understand the roles of autocrine response and regulation of sensitivity to hormonal input, we will investigate hormonal control of the activin/inhibin subunit genes, the follistatin gene, the activin receptor gene, and the GnRH receptor gene in the gonadotrope of the anterior pituitary. The role of developmental status and the interplay of hormones, growth factors, and receptors in controlling FSH beta-subunit gene expression will thus be investigated using the armamentarium of molecular, cellular, and transgenic animal technologies with a focus on understanding the role of FSH regulation in the menstrual cycle.
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