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

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

Author information

1
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK gillian.morrison@ed.ac.uk austin.smith@cscr.cam.ac.uk.
2
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
3
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK Department of Biochemistry, University of Cambridge, Cambridge, UK gillian.morrison@ed.ac.uk austin.smith@cscr.cam.ac.uk.

Abstract

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

PMID:
26675138
PMCID:
PMC4741304
DOI:
10.15252/embj.201592116
[Indexed for MEDLINE]
Free PMC Article

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