Mash1 is an essential transcription factor in neural development throughout multiple regions of the central and peripheral nervous systems. Mash1 expression is tightly regulated; it is expressed in proliferating neural stem cells and is down-regulated as the cells become post-mitotic and mature into neurons. Synthesizing results from multiple investigators on Mash1 expression and function, we hypothesize that (1) Mash1 expression is controlled by signals instructing stem cells to begin the differentiation program, (2) the specificity of function for a particular bHLH involves interacting factors, and (3) in a neural progenitor cell, Mash1 functions in transcriptional control of some but not all pathways required for neuronal differentiation. Experiments here will address these hypotheses, and identify specific molecular components upstream and downstream of this essential neural differentiation factor. We will identify transcription factors that bind the Mash1 enhancer to control Mash1 expression in the spinal neural tube. We will identify structural domains in Mash1 required for specific functions in neurogenesis and screen for interacting factors that modulate these functions. And finally, we will identify the specific regulatory pathways during neuronal differentiation controlled by Mash1 by analysis of gene expression profiles in multiple loss- and gain-of-function paradigms. Success in this research program will increase our understanding of molecular mechanisms involved in neural precursor proliferation, differentiation, and specification. This understanding is important for future therapeutic strategies in treating neurological disorders involving neuronal cell death such as Parkinson's disease, and in regenerative strategies for treatment of brain and spinal cord damage.
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