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

• Published in: Development (Cambridge) Vol. 139; no. 12; pp. 2118 - 2129
• Main Authors: Wu, Chun-I, Hoffman, Jackson A, Shy, Brian R, Ford, Erin M, Fuchs, Elaine, Nguyen, Hoang, Merrill, Bradley J
• Format: Journal Article
• Language: English
• Published: England Company of Biologists 15-06-2012
• Subjects: Animals; Anura; Basic Helix-Loop-Helix Transcription Factors - metabolism; beta Catenin - metabolism; Body Patterning - genetics; Development and Stem Cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Extremities - embryology; Eyelids - metabolism; Gastrulation - genetics; Gene Expression Regulation, Developmental; Gene Knock-In Techniques; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Limb Buds - embryology; Limb Buds - metabolism; Lymphoid Enhancer-Binding Factor 1 - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Protein Binding; Repressor Proteins - metabolism; Survival Analysis; Wnt Signaling Pathway - genetics
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.076067

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.