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

Gillian Morrison1, Roberta Scognamiglio2, Andreas Trumpp2

  • 1Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK gillian.morrison@ed.ac.uk austin.smith@cscr.cam.ac.uk.

The EMBO Journal
|December 18, 2015
PubMed

Insights

Inhibiting glycogen synthase kinase 3 (GSK3) promotes definitive endoderm formation. This process involves cMyc and β-catenin reducing Tcf7l1, which normally represses the endoderm factor FoxA2, revealing a key de-repression mechanism.

Area of Science:

  • Developmental Biology
  • Stem Cell Biology
  • Molecular Biology

Background:

  • The molecular mechanisms governing definitive endoderm formation from pluripotent stem cells are not fully elucidated.
  • While Wnt/β-catenin and Nodal signaling pathways are implicated, the precise requirements for lineage specification remain incompletely defined.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase 3 (GSK3) inhibition in definitive endoderm production.
  • To elucidate the molecular axis by which GSK3 inhibition influences endoderm specification.

Main Methods:

  • Utilized GSK3 inhibition in pluripotent stem cells.
  • Analyzed the expression and activity of key transcription factors including cMyc, β-catenin, Tcf7l1, FoxA2, and Sox17.
  • Employed genetic deletion of Tcf7l1 to assess its repressive role.

Main Results:

  • GSK3 inhibition potently enhances definitive endoderm production.
  • Elevated cMyc and β-catenin downstream of GSK3 inhibition reduce the activity of the repressor Tcf7l1.
  • Tcf7l1 normally represses FoxA2; its reduction allows FoxA2 upregulation, facilitating endoderm specification.
  • GSK3 inhibition is also required for Sox17 upregulation, indicating sequential Wnt signaling roles.

Conclusions:

  • A novel de-repression mechanism involving a cMyc/β-catenin-Tcf7l1-FoxA2 axis underlies endoderm induction.
  • This pathway highlights sequential roles for Wnt signaling in both initiating and consolidating endodermal fate.
  • The identified mechanism may be relevant to other developmental and pathological contexts.
Keywords:
FoxA2MycTcf7l1embryonic stem cellsendoderm

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