The canonical Wnt/β-catenin signaling pathway classically functions through the 
activation of target genes by Tcf/Lef-β-catenin complexes. In contrast to 
β-catenin-dependent functions described for Tcf1, Tcf4 and Lef1, the known 
embryonic functions for Tcf3 in mice, frogs and fish are consistent with 
β-catenin-independent repressor activity. In this study, we genetically define 
Tcf3-β-catenin functions in mice by generating a Tcf3ΔN knock-in mutation that 
specifically ablates Tcf3-β-catenin. Mouse embryos homozygous for the knock-in 
mutation (Tcf3(ΔN/ΔN)) progress through gastrulation without apparent defects, 
thus genetically proving that Tcf3 function during gastrulation is independent 
of β-catenin interaction. Tcf3(ΔN/ΔN) mice were not viable, and several 
post-gastrulation defects revealed the first in vivo functions of Tcf3-β-catenin 
interaction affecting limb development, vascular integrity, neural tube closure 
and eyelid closure. Interestingly, the etiology of defects indicated an indirect 
role for Tcf3-β-catenin in the activation of target genes. Tcf3 directly 
represses transcription of Lef1, which is stimulated by Wnt/β-catenin activity. 
These genetic data indicate that Tcf3-β-catenin is not necessary to activate 
target genes directly. Instead, our findings support the existence of a 
regulatory circuit whereby Wnt/β-catenin counteracts Tcf3 repression of Lef1, 
which subsequently activates target gene expression via Lef1-β-catenin 
complexes. We propose that the Tcf/Lef circuit model provides a mechanism 
downstream of β-catenin stability for controlling the strength of Wnt signaling 
activity during embryonic development.