Journal
CELL DEATH & DISEASE
Volume 12, Issue 9, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-04099-4
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Funding
- National Key Research and Development Program of China [2017YFA0103802]
- National Human Genetic Resources Sharing Service Platform [YCZYPT[2018]03-2]
- National Key R&D Program of the Ministry of Science and Technology of China [2020YFC2004400]
- National Natural Science Foundation of China [81970474, 81901514, 81970367, 81800448, 82170528]
- Key Research and Development Program of Guangdong Province [2019B020234001, 2019B020236002]
- Natural Science Foundation of Guangdong Province [2018A030313570]
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education [2020-A-005]
- Public Welfare Scientific Research Project of Zhongshan City [2019B1001]
- Shenzhen Key Medical Discipline Construction Fund [SZXK002]
- Pioneering Talents Project of Guangzhou Development Zone [2017-L163]
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SOX10 plays a crucial role in human neural crest development, affecting the generation of neural crest stem cells, differentiation of neuronal and glial cells, and cell survival. Knockout of SOX10 results in increased production of nonneural ectoderm cells during neural crest differentiation.
Animal studies have indicated that SOX10 is one of the key transcription factors regulating the proliferation, migration and differentiation of multipotent neural crest (NC), and mutation of SOX10 in humans may lead to type 4 Waardenburg syndrome (WS). However, the exact role of SOX10 in human NC development and the underlying molecular mechanisms of SOX10-related human diseases remain poorly understood due to the lack of appropriate human model systems. In this study, we successfully generated SOX10-knockout human induced pluripotent stem cells (SOX10(-/-) hiPSCs) by the CRISPR-Cas9 gene editing tool. We found that loss of SOX10 significantly inhibited the generation of p75(high)HNK1(+)/CD49D(+) postmigratory neural crest stem cells (NCSCs) and upregulated the cell apoptosis rate during NC commitment from hiPSCs. Moreover, we discovered that both the neuronal and glial differentiation capacities of SOX10(-/-) NCSCs were severely compromised. Intriguingly, we showed that SOX10(-/-) hiPSCs generated markedly more TFAP2C(+)nonneural ectoderm cells (NNE) than control hiPSCs during neural crest differentiation. Our results indicate that SOX10 is crucial for the transition of premigratory cells to migrating NC and is vital for NC survival. Taken together, these results provide new insights into the function of SOX10 in human NC development, and the SOX10-knockout hiPSC lines may serve as a valuable cell model to study the pathogenesis of SOX10-related human neurocristopathies.
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