Function of Wnt/?-catenin in counteracting Tcf3 repression through the Tcf3-?-catenin interaction.

ABSTRACT: The canonical Wnt/?-catenin signaling pathway classically functions through the activation of target genes by Tcf/Lef-?-catenin complexes. In contrast to ?-catenin-dependent functions described for Tcf1, Tcf4 and Lef1, the known embryonic functions for Tcf3 in mice, frogs and fish are consistent with ?-catenin-independent repressor activity. In this study, we genetically define Tcf3-?-catenin functions in mice by generating a Tcf3?N knock-in mutation that specifically ablates Tcf3-?-catenin. Mouse embryos homozygous for the knock-in mutation (Tcf3(?N/?N)) progress through gastrulation without apparent defects, thus genetically proving that Tcf3 function during gastrulation is independent of ?-catenin interaction. Tcf3(?N/?N) mice were not viable, and several post-gastrulation defects revealed the first in vivo functions of Tcf3-?-catenin interaction affecting limb development, vascular integrity, neural tube closure and eyelid closure. Interestingly, the etiology of defects indicated an indirect role for Tcf3-?-catenin in the activation of target genes. Tcf3 directly represses transcription of Lef1, which is stimulated by Wnt/?-catenin activity. These genetic data indicate that Tcf3-?-catenin is not necessary to activate target genes directly. Instead, our findings support the existence of a regulatory circuit whereby Wnt/?-catenin counteracts Tcf3 repression of Lef1, which subsequently activates target gene expression via Lef1-?-catenin complexes. We propose that the Tcf/Lef circuit model provides a mechanism downstream of ?-catenin stability for controlling the strength of Wnt signaling activity during embryonic development.

SUBMITTER: Wu CI 

PROVIDER: S-EPMC3357906 | biostudies-other | 2012 Jun

REPOSITORIES: biostudies-other