Brain development involves precise program of gene activation that establish specific neuronal phenotypes and the intricate patterns of connections between them. Understanding the molecular mechanisms underlying these selective programs of gene activation and repression that serially definite maturation of neurons represent a fundamental question in neurobiology. During the currant Grant period we have begun to characterize the functional roles of two families of novel neurally- expressed mammalian POU domain transcription factors discovered in this laboratory, providing evidence for the hypotheses that these factors are critical for the terminal differentiation of specific neuronal and glial phenotypes, and the patterns of the connections between them. We now propose to investigate the hypothesis that these POU domain factors, alone or combinatorially exert critical roles in early neural determination events, and to establish a technology permitting identification of critical target genes that subserve aspects of the developmental program directed by the POU domain factors in both the central and peripheral nervous systems. During the current Grant period we have cloned and characterized a series of novel genes that are components of co-activator and co-repressor complexes associated with nuclear receptors, and have documented that ligand binding switches the association of the co-repressor complex, containing histone deacetylase activity, with a co-activator complex containing histone acetylase activity. We hypothesize that these co-activator and co-repressor complexes also critically modulate the transcriptional actions of the POU domain factors in the nervous systems, and that different families of transcription factors recruit specific components of these complexes, modulated by distinct signal transcription pathways. Molecular biological and structural approaches will be employed to understand the molecular mechanisms underlying these regulatory events in the development of the nervous system. These investigations will provide insights into the molecular mechanisms by which two families of transcription factors control neural development and integrate, at the level of the nucleus, the diverse signal transduction pathways that are simultaneously activated in each neuron.
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