The molecular basis of the neuroendocrine system will be studied using a combination of molecular and genetic approaches, including the application of transgenic animal technology. Pituitary cell lineage analysis using a novel technology has permitted the identified of common precursors for somatotrophs and lactotrophs, referred to as the stem-somatotroph. We propose to generate transgenic pedigrees enriched in stem-somatotrophs, and to establish cell culture and assay systems to investigate regulatory factors that provoke stem cell differentiation. Transgenic mice expressing the GRF gene and a suicide vector will be established as a strategy to enrich stem precursors. Infection with transforming retroviruses will be utilized to generate immortalized lines. We propose to employ the thymidine kinase obliteration strategy in transgenic mice to study the corticotroph precursor, and the frequency at which post-mitotic corticotrophs are deposited in the pituitary. The cis-active regions responsible for cell-specific expression of the CRF gene will be investigated and the trans-acting factors will be identified. One brain-specific POU-domain protein that is a candidate for regulation of CRF or other hypothalamic releasing factor, gene expression will be characterized and the encoding gene will be isolated and utilized for developmental studies. In concert, these studies will further elucidate the developmental strategies that establish the cell types critical for the functional hypothalamic-pituitary axis.
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