Tcf3 Represses Wnt–β-Catenin Signaling and Maintains Neural Stem Cell Population during Neocortical Development
Open accessAbstract
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.
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TCF3 is known to repress Wnt-Beta-Catenin signaling and maintain the neural stem cell population during neocortical development.
“the HHMC-carrying transcription factor TCF3, which is known to repress Wnt-Beta-Catenin signaling and maintain the neural stem cell population during neocortical development79.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [79]
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- Authors
- Kuwahara, A., Sakai, H., Xu, Y., Itoh, Y., Hirabayashi, Y., & Gotoh, Y.
- Affiliations
- The University of Tokyo (JP)
- Corresponding author
- Hirabayashi, Yusuke
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-15
- Volume
- 9
- Issue
- 5
- Pages
- e94408
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4022625
- OpenAlex
- W1968541727
- Cited by
- 66
- References
- 71
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 4 · 2015: 4
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (23570249)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TCF3, TCF7L1, Wnt/β-catenin signaling, neocortex development, neural stem cells, neural progenitor cells, neuronal differentiation, self-renewal, Neurog1, HMG-box transcription factor, TCF1, LEF1, positive feedback loop
- MeSH terms
- Animals, Cell Differentiation, Cell Separation, Flow Cytometry, Mice, Inbred ICR, Nerve Tissue Proteins, Neurons, Stem Cells, Proto-Oncogene Proteins c-myc, In Situ Hybridization, Cell Proliferation, beta Catenin, Mice, Hepatocyte Nuclear Factor 1-alpha, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Lymphoid Enhancer-Binding Factor 1, Neural Stem Cells, Wnt Signaling Pathway, Wnt3A Protein
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