Browsing by Subject "Progenitor cell"

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    Investigating neurogenesis and cell type specification in the mammalian thalamus.
    (2012-06) Bluske, Krista K.
    The thalamus mediates a variety of important brain functions that are critical for behavior and survival. A key feature that enables the thalamus to perform such diverse functions is its parcellation into anatomically and functionally distinct groups of neurons called nuclei. The purpose of this project was to identify the origin of neuronal diversity within the thalamus by investigating the process of neurogenesis. During neurogenesis, proliferating progenitor cells begin to divide asymmetrically to generate neurons. The central hypothesis of the research presented herein is that thalamic organization requires the appropriate number and types of neurons to be generated and that these critical processes are regulated during neurogenesis. This work has characterized the different types of progenitor cells present during thalamic neurogenesis. We confirmed the existence of a special population of thalamic progenitor cells, intermediate (or basal) progenitor cells, and identified transcription factors that regulate their formation and/or maintenance. We also addressed the origin of distinct subtypes of neurons. The spatial organization of thalamic progenitor cells into two distinct progenitor domains during neurogenesis is thought to drive the formation of different subtypes of thalamic neurons. Signaling molecules have been proposed to induce the formation of distinct progenitor domains in numerous brain areas, including the thalamus. We provided a detailed characterization of components of the Wnt/β-catenin-mediated transcriptional pathway during thalamic neurogenesis. Based on the pattern of signaling activity, we hypothesized that Wnt/β-catenin-mediated transcription has a function in forming the two progenitor domains during thalamic neurogenesis. Using conditional genetic manipulations of β-catenin, we found that β-catenin-mediated transcription is required for the specification of thalamic progenitor domains. Furthermore, we found that the Wnt/β-catenin signaling pathway functions in parallel with the sonic hedgehog (Shh) signaling pathway, which had been previously shown to specify thalamic progenitor identity in an opposing manner, by independently regulating transcriptional networks in thalamic progenitor cells. Collectively, the process of neurogenesis involves the generation of the correct number of neurons by regulating asymmetric progenitor divisions and generation of appropriate neuronal subtypes through the functions of signaling pathways and transcriptional networks. These mechanisms provide a broad map for the generation and positioning of appropriate types of neurons in the correct locations within the thalamus.
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    Progenitor cell maturation and initiation of neurogenesis in the developing vertebrate neural retina.
    (2009-10) Yang, Hyun-Jin
    The mature vertebrate central nervous system is composed of an enormous number of neuronal and glial cells. A relatively small number of progenitor cells generate these cells during a finite period of time of development. Progenitor cells during early stages of central nervous system development divide so that each division produces two progeny that divide again. This `preneurogenic' mode of division is essential for the exponential increase of number of progenitor cells. Later, progenitor cells change their mode of division to `neurogenic', where one or both daughter cells produced by a division withdraw from the mitotic cycle and differentiate. This more mature, neurogenic division is critical for generation of a functional nervous system. The aim of the project described in this thesis was to understand: 1) the molecular differences that dictate the two modes of progenitor cell division, namely preneurogenic and neurogenic, 2) the mechanism that regulates the switch in the mode of division, and 3) the molecular trigger that initiates differentiation. Molecular differences between preneurogenic and neurogenic progenitor cells were identified, and are described in more detail in chapter II. The early, preneurogenic progenitor cells express the transcription factor, Sox2, and a ligand for the Notch receptor, Delta1. The more mature, neurogenic progenitor cells express Sox2 and the bHLH transcription factor, E2A, and do not express Delta1. Perturbation of Notch signaling resulted in conversion of progenitor cells from preneurogenic to neurogenic and in premature neurogenesis. Furthermore, Sonic hedgehog was found to be expressed by a subset of newly differentiating cells. Misexpression of Sonic hedgehog led to premature maturation of preneurogenic progenitor cells and neurogenesis. These results suggest that Notch signaling maintains progenitor cells in the preneurogenic state and that Sonic hedgehog initiates progenitor cell maturation. Certain proneural bHLH transcription factors were found to initiate neurogenesis, and are described in more detail in chapter III. Expression of a number of proneural bHLH factors comes up in a stereotypic temporal sequence prior to the onset of ganglion cell differentiation. Ascl1 and Neurog2 were expressed first, which was followed by expression of Neurod1 and Neurod4. Finally, Atoh7 was expressed, which preceded the appearance of ganglion cells. Individual progenitor cells expressed heterogeneous combinations of proneural genes prior to ganglion cell genesis. Misexpression of Ascl1 or Neurog2 in preneurogenic retina was sufficient to initiate ganglion cell genesis. Misexpression of Neurog2 initiated the stereotypic sequence of proneural gene expression that normally preceded ganglion cell genesis. Ascl1 expression was also sufficient to initiate ganglion cell genesis. However, it functioned by a mechanism distinct from that of Neurog2. These results suggest that ganglion cell genesis may be initiated by two different mechanisms.