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Martin, KC Sun, YE To learn better, keep the HAT on..
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Neural stem cells (NSC) are immature cells capable of generating all three major cell types in the central nervous system (CNS), neurons, astrocytes, and oligodendrocytes. That they are multipotent and have the ability to self-renew makes NSC good candidates for repairing damage in the CNS and treating neurodegenerative diseases. The research in our laboratory is aimed at understanding the molecular mechanisms by which cell-fate decisions, cell proliferation and differentiation are controlled in NSC. Both extracellular /environmental factors and cell intrinsic programs influence stem cell proliferation and differentiation. For example, our previous studies have shown that the cytokines leukemia inhibitory factor (LIF) and cilliary neurotrophic factor (CNTF), through activation of the JAK (Janus Kinase)/STAT (signal transducers and activators of transcription) signaling pathway, effectively turn on astrocyte specific genes leading NSC to differentiate into astrocytes (Science 1997, 278: 477-483). Recently, we found that a cell intrinsic factor, the basic helix-loop-helix transcription factor neurogenin1, When expressed in these cells, triggers a cascade of neuronal gene activation and at the same time suppresses glial genes, resulting in neurogenesis (Cell 2001, 104: 365-376). Changes in gene expression patterns are key events during cell cycle exit and cell differentiation. Therefore our future research will focus on elucidating, 1. the role of transcription factors such as STATs and neurogenic transcription factors in turning on and off specific gene expression programs related to proliferation and differentiation, and 2. how extracellular factors including LIF, FGF-2, PDGF and BMPs and intracellular signaling pathways (e.g. Ras-MAPkinase, PI3Kinase-AKT and JAK-STAT pathways) regulate the activities of these transcription factors. Currently we are developing a method which will allow us to efficiently derive pure NSC cultures from mouse embryonic stem cells (ES cells). Since these cells are easily genetically modifiable, we will be able to manipulate gene expression through state of the art transgenic or knockout technology in ES cells, then convert the transgenic ES cells into NSC and study the impact of these genes in the proliferation and differentiation of NSC. Understanding the molecular control of cell fate choice will allow us to direct the differentiation of NSC and to genetically engineer NSC (via ES cells) so that they may be suitable in cell replacement therapies for neurological disorders such as Alzheimer's and Parkinson's diseases.
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