| First Author | Morrison G | Year | 2016 |
| Journal | EMBO J | Volume | 35 |
| Issue | 3 | Pages | 356-68 |
| PubMed ID | 26675138 | Mgi Jnum | J:229685 |
| Mgi Id | MGI:5753001 | Doi | 10.15252/embj.201592116 |
| Citation | Morrison G, et al. (2016) Convergence of cMyc and beta-catenin on Tcf7l1 enables endoderm specification. EMBO J 35(3):356-68 |
| abstractText | The molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/beta-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 beta-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 beta-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/beta-catenin-Tcf7l1-FoxA2 axis reveals a de-repression mechanism underlying endoderm induction that may be recapitulated in other developmental and patho-logical contexts. |
