Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification
The EMBO Journal
MetadataShow full item record
Morrison, G., Scognamiglio, R., Trumpp, A., & Smith, A. (2015). Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification. The EMBO Journal, 35 356-368. https://doi.org/10.15252/embj.201592116
Molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/β-catenin and Nodal signalling are implicated but requirements for lineage specification are incompletely defined. Here we investigate the potent effect of inhibiting glycogen synthase kinase 3 (GSK3). 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. Deletion of Tcf7l1 is sufficient to allow up-regulation of FoxA2 in the presence of activin. In wild type cells Myc contributes by reducing Tcf7l1 mRNA while βcatenin acts on Tcf7l1 protein. GSK3 inhibition is required further for consolidation of endodermal fate via upregulation of Sox17, highlighting sequential roles for Wnt signalling. The identification of a Myc/βcatenin-Tcf7l1-FoxA2 axis reveals a de-repression mechanism underlying endoderm induction that may be recapitulated in other developmental and pathological contexts.
This study was funded by the Juvenile Diabetes Research Foundation International, the European Commission FP7 project BetaCellTherapy (agreement No. 241883), a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, and a University of Edinburgh Chancellor’s Fellowship awarded to GM. GM was a JDRF advanced postdoctoral fellow. AS is a Medical Research Council Professor.
EC FP7 CP (241883)
External DOI: https://doi.org/10.15252/embj.201592116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252651
Creative Commons Attribution 4.0 International License
Licence URL: http://creativecommons.org/licenses/by/4.0/