Epithelial cell plasticity drives endoderm formation during gastrulation

Nat Cell Biol. 2021 Jul;23(7):692-703. doi: 10.1038/s41556-021-00694-x. Epub 2021 Jun 24.


It is generally accepted that epiblast cells ingress into the primitive streak by epithelial-to-mesenchymal transition (EMT) to give rise to the mesoderm; however, it is less clear how the endoderm acquires an epithelial fate. Here, we used embryonic stem cell and mouse embryo knock-in reporter systems to combine time-resolved lineage labelling with high-resolution single-cell transcriptomics. This allowed us to resolve the morphogenetic programs that segregate the mesoderm from the endoderm germ layer. Strikingly, while the mesoderm is formed by classical EMT, the endoderm is formed independent of the key EMT transcription factor Snail1 by mechanisms of epithelial cell plasticity. Importantly, forkhead box transcription factor A2 (Foxa2) acts as an epithelial gatekeeper and EMT suppressor to shield the endoderm from undergoing a mesenchymal transition. Altogether, these results not only establish the morphogenetic details of germ layer formation, but also have broader implications for stem cell differentiation and cancer metastasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Blastocyst / metabolism
  • Blastocyst / physiology*
  • Cell Differentiation
  • Cell Line
  • Cell Plasticity*
  • Endoderm / cytology
  • Endoderm / metabolism
  • Endoderm / physiology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / physiology*
  • Epithelial-Mesenchymal Transition*
  • Gastrulation*
  • Gene Expression Regulation, Developmental
  • Gestational Age
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Mice
  • Mice, Transgenic
  • Mouse Embryonic Stem Cells / metabolism
  • Mouse Embryonic Stem Cells / physiology*
  • Phenotype
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Time Factors


  • Foxa2 protein, mouse
  • Snai1 protein, mouse
  • Snail Family Transcription Factors
  • Hepatocyte Nuclear Factor 3-beta