Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification

EMBO J. 2016 Feb 1;35(3):356-68. doi: 10.15252/embj.201592116. Epub 2015 Dec 16.


The molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/β-catenin and Nodal signalling have been implicated, but the requirements for lineage specification remain incompletely defined. Here, we demonstrate a potent effect of inhibiting glycogen synthase kinase 3 (GSK3) on definitive endoderm production. We find that downstream of GSK3 inhibition, elevated cMyc and β-catenin act in parallel to reduce transcription and DNA binding, respectively, of the transcriptional repressor Tcf7l1. Tcf7l1 represses FoxA2, a pioneer factor for endoderm specification. Deletion of Tcf7l1 is sufficient to allow upregulation of FoxA2 in the presence of Activin. In wild-type cells, cMyc contributes by reducing Tcf7l1 mRNA, while β-catenin acts on Tcf7l1 protein. GSK3 inhibition is further required for consolidation of endodermal fate via upregulation of Sox17, highlighting sequential roles for Wnt signalling. The identification of a cMyc/β-catenin-Tcf7l1-FoxA2 axis reveals a de-repression mechanism underlying endoderm induction that may be recapitulated in other developmental and patho-logical contexts.

Keywords: FoxA2; Myc; Tcf7l1; embryonic stem cells; endoderm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / physiology
  • Endoderm / growth & development*
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Mice
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction*
  • Transcription Factor 7-Like 1 Protein / metabolism*
  • beta Catenin / metabolism*


  • Foxa2 protein, mouse
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Tcf7l1 protein, mouse
  • Transcription Factor 7-Like 1 Protein
  • beta Catenin
  • Activins
  • Hepatocyte Nuclear Factor 3-beta
  • Glycogen Synthase Kinase 3