Neurogenesis and Gliogenesis from Ascl1 (Mash1) Expressing Progenitors in the Central Nervous System

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2010-05-14

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Kim, Euiseok Joshua

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Abstract

For the functional architecture of the central nervous system, a small population of neural stem cells generates the correct numbers and types of neurons, oligodendrocytes and astrocytes in a precisely coordinated manner. Basic helix-loop-helix (bHLH) transcription factors play central roles in determining distinct neural cell fates and thus contribute to mechanisms controlling neural cell type diversity during the embryogenesis. Fundamental to understanding nervous system formation is to uncover links between early cell type specification mechanisms, the developmental dynamics of each lineage, and the contributions of specific molecules to these processes to form the mature nervous system structures. Ascl1 (previously Mash1) is a bHLH transcription factor essential for neuronal differentiation and neural sub-type specification. Ascl1 is present in proliferating progenitor cells but these cells are actively differentiating as evidenced by their rapid migration out of germinal zones. Although it has been studied for its role in several neural lineages, the full complement of lineages arising from Ascl1 progenitor cells and the molecular mechanism of Ascl1’s functions are not completely understood. Using an inducible Cre-flox genetic fate-mapping strategy, Ascl1 lineages were determined in both the embryonic and adult central nervous system. In chapter two, the fate of Ascl1+ progenitor cells throughout the brain was described. Depending on the temporal and spatial context during embryogenesis, Ascl1+ cells contribute to distinct neuronal and glial cells in each major brain division. In chapter three, by labeling Ascl1+ progenitor cells at distinct phases of their development, I delineated the temporal lineage relationship of distinct subtypes of neurons and glia in the developing spinal cord. Two spatially and temporally distinct Ascl1+ progenitor populations contribute differentially to inhibitory dILA and excitatory dILB neurons in the dorsal spinal cord. At later stages of embryogenesis, Ascl1+ progenitors are restricted to glial lineages giving rise to both astrocytes and oligodendrocytes. Analysis of conditional mutants of Ascl1 demonstrated that Ascl1 is required for only one division of each lineage. Loss of Ascl1 results in a reduction of inhibitory dILA neurons and oligodendrocytes, but not excitatory dILB neurons and astrocytes. In chapter four, the physiological functions of Nicastrin in gliogenesis were investigated. Nicastrin is a requisite subunit of the !-secretase complex essential for activating Notch signaling pathway. Conditional mutant of Nicastrin leads to the increased level of oligodendrocytes lineage markers in the neural tube, the opposite phenotype of that for Ascl1. Thus, I propose that Notch signaling in constraining levels of Ascl1 is required in oligodendrogenesis. In chapter five, I revealed that Ascl1 is a common molecular marker of early progenitors of both neurons and oligodendrocytes in the adult brain, and these Ascl1 defined progenitors mature with distinct dynamics in different brain regions. In this thesis, I define Ascl1 as a neural differentiation factor crucial for neural cell type diversification, playing important roles in cell differentiation and subtype specification at several different nodes of cell fate decisions throughout neurodevelopment.

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