SOX10 ablation severely impairs the generation of postmigratory neural crest from human pluripotent stem cells.

Abstract

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 p75highHNK1+/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.

• Authors: Xingqiang Lai, Jia Liu, Zhengwei Zou, Yina Wang, Ye Wang, Xiao Liu, Weijun Huang, Yuanchen Ma, Qian Chen, Fugui Li, Guifu Wu, Weiqiang Li, Weijia Wang, Yong Yuan, Boxiong Jiang
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 9 Pg. 814 (08 27 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34453037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Biomarkers
• RNA, Guide
• SOX10 protein, human
• SOXE Transcription Factors

Topics

• Apoptosis (genetics)
• Base Sequence
• Biomarkers (metabolism)
• Cell Differentiation (genetics)
• Cell Movement (genetics)
• Cell Shape (genetics)
• Epithelial Cells (metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Developmental
• Humans
• Induced Pluripotent Stem Cells (cytology, metabolism)
• Neural Crest (cytology)
• Neurons (cytology, metabolism)
• RNA, Guide, Kinetoplastida (genetics)
• SOXE Transcription Factors (deficiency, metabolism)
• Schwann Cells (cytology)