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

TitleConvergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification.
Publication TypeJournal Article
Year of Publication2016
AuthorsMorrison GM, Scognamiglio R, Trumpp A, Smith A
JournalEMBO J
Volume35
Issue3
Pagination356-68
Date Published2016 Jan 1
ISSN1460-2075
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.

DOI10.15252/embj.201592116
Alternate JournalEMBO J.
PubMed ID26675138
PubMed Central IDPMC4741304
Publication institute
CRM