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| Neural Stem Cells with SOX2 Gene are Development Gatekeepers |
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| SciMed - Neuroscience | |
| TS-Si News Service | |
| Sunday, 08 May 2011 15:00 | |
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La Jolla, CA, USA. A gene called SOX2 acts as a stem cell gatekeeper — only cells expressing it have the potential to become neurons.
Research into this process has already informed scientific understanding of human development and birth anomalies, and could lead to improved therapies for neurocristopathies, the class of pathologies in the tissues containing cells derived from embryonic neural crest cells. Early in embryonic development, the neural crest — a transient group of stem cells — gives rise to parts of the  nervous system and several other tissues. But little is known about what determines which cells become neurons and which become other cell types. Scientists recently found that expression of a gene called SOX2 maintains the potential for neural crest stem cells to become neurons in the peripheral nervous system, where they interface with muscles and other organs. Their results appear in the journal Cell Stem Cell.SOX2 Role In Sensory NeurogenesisNeural crest cells are multipotent stem cells that originate in the future spinal cord in vertebrates. They emigrate from the developing neural tube into the embryo, yielding a large and divere range of cell types and tissues. Neural crest derivatives include support for gene expression within the migrating cells of both male and female embryos, and the genital ridge of male embryos when development of sex genitalia is triggered by the body plan.Click Pic for DetailsThe SOX2 gene encodes a transcription factor, a type of protein that switches other genes on or off. SOX2 is one of two key genes researchers use to generate induced pluripotent stem cells (iPSCs), which are capable of differentiating into all cell types for research and potential therapeutic applications.Dr. Alexey Terskikh is assistant professor at the Sanford-Burnham Medical Research Institute (Sanford-Burnham) and active in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center. "In this study, we looked at SOX2's role in cells of the peripheral nervous system and discovered that it's required to sustain multipotency — the ability to differentiate into several cell types in the peripheral nervous system, including neurons and glia." Using an embryonic stem cell model, Dr. Terskikh and colleagues showed that stem cells in the developing nervous system start out with SOX2, but lose it at the stage when they are considered migratory neural crest cells. Later, as neural crest stem cells aggregate at a subsequent point in development, SOX2 is regained only by those cells fated to become neurons. Neural crest stem cells that remain SOX2-free differentiate into other cell types, but never become neurons. To determine how SOX2 controls this stage in nervous system development, the researchers looked at the genes it acts upon. They found that SOX2 switches on neurogenin-1 and Mash-1, two genes that support neuronal survival in both the central and peripheral nervous systems. "If we prevent neural crest stem cells from re-expressing SOX2, we don't get neurons. If we try to push these SOX2-deficient cells to become neurons, they die, but they can readily give rise to glia or smooth muscle cells," Dr. Terskikh said. "We think that one function of SOX2 is to keep cells multipotent or pluripotent for one reason — if they need to become a neuron later in development. We hope this finding will be useful to researchers studying neural crest development and stem cell differentiation."Further research could help better inform therapies aimed at neurocristopathies such as microphthamia and CHARGE syndrome. FundingDr. Terskikh is supported by the California Institute for Regenerative Medicine (CIRM). Co-authors of this study include Flavio Cimadamore, Elena Giusto, Ksenia Gnedeva, Giulio Cattarossi, Amber Miller and Laurence M. Brill at Sanford-Burnham, Katherine Fishwick and Marianne Bronner-Fraser at the California Institute of Technology and Stefano Pluchino from the Institute of Experimental Neurology, IRCCS, in Italy.
CitationHuman ESC-Derived Neural Crest Model Reveals A Key Role For SOX2 In Sensory Neurogenesis. Flavio Cimadamore, Katherine Fishwick, Elena Giusto, Ksenia Gnedeva, Giulio Cattarossi, Amber Miller, Stefano Pluchino, Laurence M. Brill, Marianne Bronner-Fraser, Alexey V. Terskikh. Cell Stem Cell 2011; 8(5): 538-551. doi:10.1016/j.stem.2011.03.011
Download PDF Highlights ● SOX2 downregulation is sufficient to induce EMT/NC emigration ● SOX2 is downregulated in migratory NC, but re-expressed in nascent neurons in DRG ● SOX2 directly binds to NGN1 and MASH1 promoters and is required for their expression ● SOX2 controls NGN1-dependent sensory neurogenesis, but neither Schwann cells' nor smooth muscles' fates Abstract The transcription factor SOX2 is widely known to play a critical role in the central nervous system; however, its role in peripheral neurogenesis remains poorly understood. We recently developed an hESC-based model in which migratory cells undergo epithelial to mesenchymal transition (EMT) to acquire properties of neural crest (NC) cells. In this model, we found that migratory NC progenitors downregulate SOX2, but then start re-expressing SOX2 as they differentiate to form neurogenic dorsal root ganglion (DRG)-like clusters. SOX2 downregulation was sufficient to induce EMT and resulted in massive apoptosis when neuronal differentiation was induced. In vivo, downregulation of SOX2 in chick and mouse NC cells significantly reduced the numbers of neurons within DRG. We found that SOX2 binds directly to NGN1 and MASH1 promoters and is required for their expression. Our data suggest that SOX2 plays a key role for NGN1-dependent acquisition of neuronal fates in sensory ganglia.
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| Last Updated on Sunday, 08 May 2011 15:20 |
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