Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal

Nat Cell Biol. 2011 Jun 19;13(7):762-70. doi: 10.1038/ncb2283.

Abstract

The co-occupancy of Tcf3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that Tcf3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signalling suggested Tcf3-β-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression regulates ESC self-renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of Tcf3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both Tcf3-β-catenin and Tcf1-β-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized β-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Line
  • Cell Proliferation* / drug effects
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism*
  • Gene Expression Regulation, Developmental
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Mice
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Transcription, Genetic
  • Transfection
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CTNNB1 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Protein Kinase Inhibitors
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Tcf3 protein, mouse
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • Glycogen Synthase Kinase 3

Associated data

  • GEO/GSE27455