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

Development. 2012 Jun;139(12):2118-29. doi: 10.1242/dev.076067. Epub 2012 May 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Body Patterning / genetics
  • 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
  • beta Catenin / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hedgehog Proteins
  • Lymphoid Enhancer-Binding Factor 1
  • Repressor Proteins
  • Shh protein, mouse
  • Tcf3 protein, mouse
  • beta Catenin