A 3D model of a human epiblast reveals BMP4-driven symmetry breaking

Nat Cell Biol. 2019 Jul;21(7):900-910. doi: 10.1038/s41556-019-0349-7. Epub 2019 Jul 1.

Abstract

Breaking the anterior-posterior symmetry in mammals occurs at gastrulation. Much of the signalling network underlying this process has been elucidated in the mouse; however, there is no direct molecular evidence of events driving axis formation in humans. Here, we use human embryonic stem cells to generate an in vitro three-dimensional model of a human epiblast whose size, cell polarity and gene expression are similar to a day 10 human epiblast. A defined dose of BMP4 spontaneously breaks axial symmetry, and induces markers of the primitive streak and epithelial-to-mesenchymal transition. We show that WNT signalling and its inhibitor DKK1 play key roles in this process downstream of BMP4. Our work demonstrates that a model human epiblast can break axial symmetry despite the absence of asymmetry in the initial signal and of extra-embryonic tissues or maternal cues. Our three-dimensional model is an assay for the molecular events underlying human axial symmetry breaking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bone Morphogenetic Protein 4 / metabolism*
  • Cell Polarity / physiology
  • Epithelial-Mesenchymal Transition
  • Gastrulation / physiology
  • Gene Expression Regulation, Developmental / physiology*
  • Germ Layers / metabolism*
  • Humans
  • Primitive Streak / embryology
  • Primitive Streak / metabolism*
  • Signal Transduction / physiology
  • Tissue Culture Techniques*

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4