Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors

Dev Cell. 2017 Sep 11;42(5):514-526.e7. doi: 10.1016/j.devcel.2017.07.021. Epub 2017 Aug 17.

Abstract

The spinal cord and mesodermal tissues of the trunk such as the vertebral column and skeletal musculature derive from neuro-mesodermal progenitors (NMPs). Sox2, Brachyury (T), and Tbx6 have been correlated with NMP potency and lineage choice; however, their exact role and interaction in these processes have not yet been revealed. Here we present a global analysis of NMPs and their descending lineages performed on purified cells from embryonic day 8.5 wild-type and mutant embryos. We show that T, cooperatively with WNT signaling, controls the progenitor state and the switch toward the mesodermal fate. Sox2 acts antagonistically and promotes neural development. T is also involved in remodeling the chromatin for mesodermal development. Tbx6 reinforces the mesodermal fate choice, represses the progenitor state, and confers paraxial fate commitment. Our findings refine previous models and establish molecular principles underlying mammalian trunk development, comprising NMP maintenance, lineage choice, and mesoderm formation.

Keywords: NMP; chromatin; lineage choice; mesoderm; mouse; neuro-mesodermal progenitors; neuroectoderm; single-cell analysis; transcriptome; trunk development.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Lineage / genetics*
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / genetics
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Mesoderm / cytology*
  • Mice
  • Models, Biological
  • Neurons / cytology*
  • Neurons / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Single-Cell Analysis
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Transcription Factors / metabolism
  • Wnt Signaling Pathway / genetics

Substances

  • Chromatin
  • Fetal Proteins
  • SOXB1 Transcription Factors
  • T-Box Domain Proteins
  • Tbx6 protein, mouse
  • Transcription Factors
  • Brachyury protein