The anterior pituitary plays a central role in the regulation of reproductive function, growth, lactation, stress response, and endocrine homeostasis. The pituitary also serves as an excellent model in which to study the complex molecular interactions involved in development and organogenesis in mammalian systems. The anterior lobe rises from the somatic ectoderm by formation of Rathke's pouch. Within this primitive organ five distinct endocrine cell types arise. These are, in developmental order of appearance: corticotropes which produce pro- opiomelanocortin, thyrotropes which produce thyrotropin-releasing hormone (TSH), gonadotropes which produce both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), somatotropes which produce growth hormone, and lactotropes which produce prolactin. Substantial information is available concerning the molecular events important for regulation of growth hormone and prolactin gene expression; however, much less is known about the determination of pituitary gene expression of the family of glycoprotein hormones, LH, FSH,and TSH. These hormones are heterodimeric proteins composed of a common a subunit and distinct beta subunits encoded by individual gene. The temporal appearance of the individual subunits is not coordinated and indicated that the alpha-subunit gene may be expressed in a common early progenitor cell for all endocrine lineages of the anterior pituitary. Thus, development of the individual cell types may involve independent activation of specific hormone genes coupled with specific restriction of gene expression. The molecular basis of regulation of the LH and FSH genes in gonadotropes could not be effectively investigated heretofore due to lack of appropriate cell lines. Tumors derived by pituitary-specific expression of the SV40 T- antigen oncogene in transgenic mice have allowed us to isolate clonal cell lines representing cells in the developmental lineage of the gonadotrope which express either the common alpha-subunit or both the alpha and LH beta-subunit genes. In this proposal, we investigate three major issues: A. The mechanisms of developmental and tissue-specific control of the gonadotropin genes in pituitary cells, including the roles of both transcriptional activation and restriction in directing unique patterns of gene expression. B. The molecular basis of hormonal regulation of gonadotropin gene expression, with emphasis on induction of gene expression by hypothalamic gonadotropin-releasing hormone and repression by gonadal steroids. C. The molecular events determining the developmental lineage of the gonadotrope in the anterior pituitary, utilizing approaches transgenic mice including targeted immortalization, cell ablation, and ectopic expression of regulatory proteins. These investigations will lead to detailed understanding of the molecular events governing the developmental and hormonal regulation of the gonadotrope and pituitary development.
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