Human ESC-Derived Neural Crest Model Reveals a Key Role for SOX2 in Sensory Neurogenesis

Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell stem cell (Impact Factor: 22.27). 05/2011; 8(5):538-51. DOI: 10.1016/j.stem.2011.03.011
Source: PubMed

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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    • "During the developmental stage of peripheral nervous system (PNS), Sox2 is expressed in neural crest stem cells and regulates the differentiation to DRG neurons [9] [10]. Sox2 is also expressed in immature Schwann cells and inhibits myelination [11]. "
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    ABSTRACT: Sox2 is a transcriptional factor expressed in neural stem cells. It is known that Sox2 regulates cell differentiation, proliferation and survival of the neural stem cells. Our previous study showed that Sox2 is expressed in all satellite glial cells of the adult rat dorsal ganglion. In this study, to examine the role of Sox2 in satellite glial cells, we establish a satellite glial cell-enriched culture system. Our culture method succeeded in harvesting satellite glial cells with the somata of neurons in the dorsal root ganglion. Using this culture system, Sox2 was downregulated by siRNA against Sox2. The knockdown of Sox2 downregulated ErbB2 and ErbB3 mRNA at 2 and 4 days after siRNA treatment. MAPK phosphorylation, downstream of ErbB, was also inhibited by Sox2 knockdown. Because ErbB2 and ErbB3 are receptors that support the survival of glial cells in the peripheral nervous system, apoptotic cells were also counted. TUNEL-positive cells increased at 5 days after siRNA treatment. These results suggest that Sox2 promotes satellite glial cell survival through the MAPK pathway via ErbB receptors. Copyright © 2015. Published by Elsevier Inc.
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    • "CHD7 role in neural crest development was further confirmed in vivo, using Xenopus embryos, showing the evolutionary conserved function of this gene. Similar approaches have established a crucial role for SOX2 in human neural crest epithelial-to-mesenchymal transition (EMT), migration and subsequent neurogenesis (Cimadamore et al., 2011). Furthermore, these approaches will be useful for modeling human pathologies related to neural crest defects in vitro, and designing therapeutical strategies. "
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