The precise differentiation of neurons within the vertebrate nervous system is specified by a complex genetic program of transcription factor interactions, as well as modulation of these interactions by environmental cues. Although the roles of many specific transcription factors and signaling pathways have been characterized in neuronal differentiation, our understanding of the detailed mechanisms involved is still far from complete. This proposal employs genomic sequence information of several mammalian genomes, the fundamental observation that vertebrate nervous system development is highly conserved throughout evolution, and recent developments in functional genomics to propose a high-throughput functional genomic analysis of neuronal differentiation. The hypothesis to be tested in this proposal is that evolutionary conserved sequences surrounding genes induced during neuronal differentiation are important to the orchestration of neuronal induction. In the first specific aim, P19 embryonic carcinoma cells will be induced to undergo neuronal differentiation and microarray hybridization studies will be carried out to identify genes that are transcriptionally regulated. In the second specific aim, evolutionarily conserved non-genic sequences (CNGs) of the mouse genome, that have recently been proposed to represent clusters of cis- regulatory sequences, will be analyzed for transcriptional regulation using a high-throughput microarray transfection method in P19 cells. In the third specific aim, the role of protein kinases and transcription factors in the regulation of these cis-acting sequences will be characterized. The end result of these studies will be a detailed understanding of important cis-regulatory sequences of neuronally induced genes and the role of specific signal transduction pathways in the modulation of their transcriptional activation. The results of these studies will be important for future therapeutic approaches to treatment of neurodegenerative diseases including Alzheimer's and Parkinson's diseases. ? ?
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