bHLH transcription factors function during neurogenesis and neuronal specification, and are essential for the development of multiple neuronal lineages in the central and peripheral nervous systems. In order to fulfill these essential functions, bHLH factor expression is precisely controlled both spatially and temporally. This precise control ensures the development of a nervous system with the correct composition and organization of neuronal cell-types. Thus, both the regulation and function of these factors are critical for normal neural development. The bHLH factors Ngn1, Ngn2, and P48 are expressed in the proliferative zone of the neural tube and are required for brain and spinal cord development. The goal of this proposal is to define molecular mechanisms controlling neurogenesis and neuronal specification using these specific bHLH factors as model regulators of this developmental process. In addition, given the region specific expression of the different bHLH factors, they will be used to map lineages from the embryonic neural tube to the adult brain and spinal cord. To attain these goals, we will identify distinct regulatory sequences within the ngnl gene that control temporal and spatial expression particularly in the dorsal telencephalon and dorsal root ganglia. Using a novel Ngn1-Cre expressing mouse strain, we will trace the neural lineage of Ngn1-expressing progenitor cells from the embryo to postnatal stages, and test the requirement for Ngn1 in these lineages. We will define the functions of the bHLH factor P48 in dorsal neural tube particularly with respect to the function and regulation of the other bHLH factors present. And finally, we will identify Ngn1 interacting factors in the dorsal versus ventral spinal neural tube that may act in combination with Ngn1 to control neuronal specification. Success in this research program will increase our understanding of molecular mechanisms involved in neural precursor proliferation, differentiation, and specification. These studies have broad implications for understanding the underlying biology of multiple nervous system disorders, and may provide insight into future rationale for therapeutic strategies particularly as they relate to stem cell manipulation.
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