The neuroendocrine cells of the hypothalamus and the multiple endocrine cell lineages of the anterior pituitary are central to coordinating endocrine function. Defining the relationships and functional integration of these endocrine cell types is essential for understanding the complex interplay of widely differing tissues and organ systems regulated by endocrine effectors.
The aims of this proposal investigate the developmental relationships of the pituitary endocrine cells and their relationship to the neuroendocrine hypothalamus. Recent data have demonstrated the role of the transcription factor GATA-4, a member of a family of developmentally regulated transcription factors, in the regulation of the alpha-glycoprotein hormone subunit gene in pituitary gonadotropes and of the gonadotropin-releasing hormone (GnRH) gene in hypothalamus. Studies of GATA-4 throughout development have identified this factor in embryonic progenitors to both the GnRH neurons and the pituitary gonadotropes. This proposal seeks to describe the extent of GATA factor expression in the hypothalamus and pituitary and to examine the expression of GATA-4 during development. In the first aim, we propose to define the extent of GATA-4 gene expression in cultured cell lines derived from the various pituitary endocrine lineages and in the mature and developing mouse pituitary. We will also investigate the transcriptional determinants specifying expression of GATA-4 in pituitary cells as well as examine potential regulatory pathways affecting GATA-4 expression. In the second aim, we propose parallel studies examining the extent of the expression of GATA-4 in the mature and developing hypothalamus. We also seek to determine the regulatory elements directing cell type-specific expression of GATA-4 in GnRH neurons, as well as possible regulation of the GATA-4 gene by known regulators of GnRH neurons. The identification of common elements regulating GATA-4 expression in neuroendocrine and pituitary cells will provide a basis for investigating the molecular mechanisms regulating the differentiation of these differing but functionally highly integrated cells. Further, the third aim proposes the development of a transgenic mouse model system expressing a reporter gene under the regulation of the GATA-4 promoter. This model system will facilitate studies of the regulation of GATA-4 in the adult and embryonic mouse. Overall, the proposed studies seek to develop a model for the differentiation of important endocrine tissues by examination of shared regulatory factors that are essential for their development.
| Lawson, Mark A; Macconell, Leigh A; Kim, Jinah et al. (2002) Neuron-specific expression in vivo by defined transcription regulatory elements of the GnRH gene. Endocrinology 143:1404-12 |
| Sosnowski, R; Mellon, P L; Lawson, M A (2000) Activation of translation in pituitary gonadotrope cells by gonadotropin-releasing hormone. Mol Endocrinol 14:1811-9 |
| MacConell, L A; Lawson, M A; Mellon, P L et al. (1999) Activin A regulation of gonadotropin-releasing hormone synthesis and release in vitro. Neuroendocrinology 70:246-54 |
| Lawson, M A; Mellon, P L (1998) Expression of GATA-4 in migrating gonadotropin-releasing neurons of the developing mouse. Mol Cell Endocrinol 140:157-61 |
| Lawson, M A; Buhain, A R; Jovenal, J C et al. (1998) Multiple factors interacting at the GATA sites of the gonadotropin-releasing hormone neuron-specific enhancer regulate gene expression. Mol Endocrinol 12:364-77 |
