Abnormal development of the nervous system is thought to underlie many complex neurological disorders. In the past decade, research in several vertebrate organisms has shown the bHLH transcription factor Ascl1 (previously Mash1) is essential for neuronal differentiation and sub-type specification for the generation of multiple neuronal cell-types throughout the brain, spinal cord, and autonomic nervous system, as well as neuroendocrine and sensory cells. Recent studies show that Ascl1 is also present in cells fated to become oligodendrocytes. The focus of this research project is to understand the regulation and function of Ascl1 in the generation of these diverse neural cell-types. First, elucidation of mechanisms regulating Ascl1 levels is critical for understanding cell number control since Ascl1 function is placed at a critical point in the transition between cycling progenitor cells and post-mitotic neural cells. Experiments testing the importance of sequences conserved across multiple species will be used to identify the regulatory mechanisms controlling Ascl1 expression. Second, Ascl1 is one of the few transcription factors known to regulate diversity in the CNS, however, because Ascl1 expression is transient, and because cells can undergo extensive migrations as they differentiate, it has been difficult to identify the full complement of cell-types in the adult brain that are in the Ascl1 lineage. An in vivo inducible genetic fate-mapping strategy will be used to identify the full complement of cell-types in the brain that have their origin in an Ascl1-expressing cell. And finally, the function of Ascl1 in oligodendrogenesis will be examined for comparison to its function in neurogenesis. We will identify and compare transcriptional targets of Ascl1 activity in spatially and temporally distinct Ascl1- expressing tissues to uncover the mechanism of Ascl1 function. These experiments will address intrinsic molecular mechanisms used to generate the correct number and type of neurons and oligodendrocytes in the CNS. Relevance: Since Ascl1 is critical in transitioning cells from a progenitor state to a differentiated state, studies of the regulation and function of Ascl1 hold significance for their fundamental contributions to multiple areas of concern to public health such as 1) manipulation of neural stem cells, 2) the underlying biology in multiple developmental disorders of the nervous system such as autism and schizophrenia, and 3) in cancers originating in neural tissue such as glioblastoma and neuroblastoma. ? ? ?
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