SOX21 Ensures Rostral Forebrain Identity by Suppression of WNT8B during Neural Regionalization of Human Embryonic Stem Cells

Stem Cell Reports. 2019 Dec 10;13(6):1038-1052. doi: 10.1016/j.stemcr.2019.10.013. Epub 2019 Nov 21.

Abstract

The generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in humans is poorly understood. Here, we applied a rostrocaudal patterning system from hESCs to dissect global transcriptional networks controlling early neural regionalization. We found that SOX21 is required for rostral forebrain fate specification. SOX21 knockout led to activation of Wnt signaling, resulting in caudalization of regional identity of rostral forebrain neural progenitor cells. Moreover, we identified WNT8B as a SOX21 direct target. Deletion of WNT8B or inhibition of Wnt signaling in SOX21 knockout neural progenitor cells restored rostral forebrain identity. Furthermore, SOX21 interacted with β-catenin, interfering with the binding of TCF4/β-catenin complex to the WNT8B enhancer. Collectively, these results unveil the unknown role of SOX21 and shed light on how a transcriptional factor modulates early neural regionalization through crosstalk with a key component of Wnt signaling.

Keywords: SOX21; WNT8B; Wnt signaling; forebrain; human embryonic stem cells; neural regionalization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Differentiation / genetics
  • Computational Biology / methods
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Prosencephalon / cytology
  • Prosencephalon / metabolism*
  • SOXB2 Transcription Factors / chemistry
  • SOXB2 Transcription Factors / metabolism*
  • Wnt Proteins / chemistry
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway

Substances

  • SOX21 protein, human
  • SOXB2 Transcription Factors
  • WNT8B protein, human
  • Wnt Proteins