BHLH TRANSCRIPTION FACTORS IN NEURAL DEVELOPMENT

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DESCRIPTION(Applicant's abstract reproduced verbatim): Four members of the neural specific bHLH family of transcription factors, NGN1, NGN2, MASH1 and MATH1, are essential for development of the mammalian nervous system. These factors are expressed in proliferating neural precursors in precise patterns within the developing neural tube, and their expression is extinguished as the cells become postmitotic and differentiate. From previous studies, it is clear that MASH1 and ngnl/2 have distinct expression domains within the spinal neural tube. However, ngnl and ngn2 have apparently overlapping domains, and in the dorsal neural tube these may overlap with MATH1. It is not clear if these bHLH factors are co-expressed or whether each marks a specific cell type within overlapping domains. We hypothesize that neural precursors that adopt distinct cell fates require a unique combination of bHLH factors for correct differentiation and specification. In addition, the upstream factors that regulate the precise temporal and spatial expression of this class of bHLH proteins may control the transition from a neural stem cell to a differentiating neural precursor. To address these hypotheses, the overlap of expression at a single cell level between ngnl, ngn2, MATH1, and MASH1 in the developing spinal neural tube, and the functional requirement for each bHLH factor in the development of identified neurons will be determined. The mechanisms functioning to obtain precise temporal and spatial expression of these genes will be elucidated to increase understanding into neural precursor proliferation and specification. These experiments will reveal insights into the organization and role of the neural specific bHLH factors in the spinal neural tube, and into the intrinsic mechanisms controlling neural development.