Tcf3 Represses Wnt-β-catenin Signaling and Maintains Neural Stem Cell Population During Neocortical Development

PLoS One. 2014 May 15;9(5):e94408. doi: 10.1371/journal.pone.0094408. eCollection 2014.

Abstract

During mouse neocortical development, the Wnt-β-catenin signaling pathway plays essential roles in various phenomena including neuronal differentiation and proliferation of neural precursor cells (NPCs). Production of the appropriate number of neurons without depletion of the NPC population requires precise regulation of the balance between differentiation and maintenance of NPCs. However, the mechanism that suppresses Wnt signaling to prevent premature neuronal differentiation of NPCs is poorly understood. We now show that the HMG box transcription factor Tcf3 (also known as Tcf7l1) contributes to this mechanism. Tcf3 is highly expressed in undifferentiated NPCs in the mouse neocortex, and its expression is reduced in intermediate neuronal progenitors (INPs) committed to the neuronal fate. We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay. Tcf3 bound to the promoter of the proneural bHLH gene Neurogenin1 (Neurog1) and repressed its expression. Consistent with this, Tcf3 repressed neuronal differentiation and increased the self-renewal activity of NPCs. We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7) and Lef1, positive mediators of Wnt signaling, in NPCs. Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Cell Separation
  • Flow Cytometry
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • In Situ Hybridization
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Mice
  • Mice, Inbred ICR
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / cytology*
  • Neurons / cytology*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Stem Cells / cytology
  • Wnt Signaling Pathway*
  • Wnt3A Protein / metabolism*
  • beta Catenin / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CTNNB1 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-myc
  • Tcf3 protein, mouse
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • Neurog1 protein, mouse

Grant support

This work was supported by Grants-in-Aid for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, Innovative Areas ‘Neural Diversity and Neocortical Organization’ of MEXT, by Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency, by the Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.