title: Function of Wnt/β-catenin in counteracting Tcf3 repression through the Tcf3-β-catenin interaction.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Chun-I
authors.initials: CI
authors.lastname: Wu
authors.forename: Jackson A
authors.initials: JA
authors.lastname: Hoffman
authors.forename: Brian R
authors.initials: BR
authors.lastname: Shy
authors.forename: Erin M
authors.initials: EM
authors.lastname: Ford
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
authors.forename: Hoang
authors.initials: H
authors.lastname: Nguyen
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Merrill
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019521:Body Patterning / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D005143:Eyelids / Q000378:metabolism; D054262:Gastrulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018878:Limb Buds / Q000196:embryology / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D016019:Survival Analysis; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D012097:Repressor Proteins; D051176:beta Catenin; C465570:Shh protein, mouse; C075668:Tcf3 protein, mouse