Understanding the physiological mechanisms of brain development and maintenance of neuronal phenotype is central to elucidating abnormalities that may undertie severe neurological and psychiatric abnormalities. The molecular mechanisms responsible for activating gene expression responsible for establishing normal neural phenotypes and patterns of connections are unknown. Identification of the factors normally dictating these developmental events is critical for understanding abnormalities in brain development and function. We have recently identified a large family of brain-specific transcription factors containing a novel domain, referred to as the POU-domain. The identification of members of the POU-domain family expressed in discrete temporal and spatial patterns during neural development, referred to as Brn-1, Brn-2, Brn-3, Brn4, and Tst-1. Their expression in the cortex, sensory ganglia, hippocampus and hypothalamus permit a strategy to investigate transcriptional activation and regulation of genes establishing distinct neuronal phenotypes with the central nervous system. The functions of the POU-domain proteins for brain development will be investigated by targeting ectopic expression in transgenic mice, by creating POU-domain gene negative transgenic animals, and by characterizing known mutants for defects in expression of functional POU-domain proteins. A detailed analysis of the POU-domain structure and function, protein interactions, hormone-induced covalent modifications, and regulatory DNA cognate elements will be performed. Additional positive and restrictive factors required for cell-specific expression have been characterized and cloned, permitting investigation of combinatorial codes of cell-specific gene activation. This cis-active elements dictating the ontogeny of POU-domain gene activation during pituitary development will be established, the responsible trans-activating factors identified, and their encoding genes isolated. Retinoic acid receptor regulates expression of specific POU-domain genes, binding to specific cis-active DNA recognition elements. This binding appears to require interaction with another protein(s), referred to as comorphogens. A series of putative factors that can form heterodimers with the retinoic acid receptor, and that are required for binding and developmental function in neural cell lines, will be identified and structurally characterized, and their functional roles in morphogenesis will be defined. These studies should provide insights into the complex interactions of regulatory factors that control development and homeostatic control characteristic of the mammalian neuroendocrine system. These investigations will ultimately leave clear implications to problems of mental health, and these issues can be effectively explored based on the initial, proposed investigations.
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