| First Author | Wu CI | Year | 2012 |
| Journal | Development | Volume | 139 |
| Issue | 12 | Pages | 2118-29 |
| PubMed ID | 22573616 | Mgi Jnum | J:185554 |
| Mgi Id | MGI:5429140 | Doi | 10.1242/dev.076067 |
| Citation | Wu CI, et al. (2012) Function of Wnt/beta-catenin in counteracting Tcf3 repression through the Tcf3-beta-catenin interaction. Development 139(12):2118-29 |
| abstractText | The canonical Wnt/beta-catenin signaling pathway classically functions through the activation of target genes by Tcf/Lef-beta-catenin complexes. In contrast to beta-catenin-dependent functions described for Tcf1, Tcf4 and Lef1, the known embryonic functions for Tcf3 in mice, frogs and fish are consistent with beta-catenin-independent repressor activity. In this study, we genetically define Tcf3-beta-catenin functions in mice by generating a Tcf3DeltaN knock-in mutation that specifically ablates Tcf3-beta-catenin. Mouse embryos homozygous for the knock-in mutation (Tcf3(DeltaN/DeltaN)) progress through gastrulation without apparent defects, thus genetically proving that Tcf3 function during gastrulation is independent of beta-catenin interaction. Tcf3(DeltaN/DeltaN) mice were not viable, and several post-gastrulation defects revealed the first in vivo functions of Tcf3-beta-catenin interaction affecting limb development, vascular integrity, neural tube closure and eyelid closure. Interestingly, the etiology of defects indicated an indirect role for Tcf3-beta-catenin in the activation of target genes. Tcf3 directly represses transcription of Lef1, which is stimulated by Wnt/beta-catenin activity. These genetic data indicate that Tcf3-beta-catenin is not necessary to activate target genes directly. Instead, our findings support the existence of a regulatory circuit whereby Wnt/beta-catenin counteracts Tcf3 repression of Lef1, which subsequently activates target gene expression via Lef1-beta-catenin complexes. We propose that the Tcf/Lef circuit model provides a mechanism downstream of beta-catenin stability for controlling the strength of Wnt signaling activity during embryonic development. |
