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Cited by 648Neurogenesis and neuroplasticity mechanismsWnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene Regulation

Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis

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Kuwabara, Tomoko, Hsieh, Jenny, Muotri, Alysson, Yeo, Gene, Warashina, Masaki, Lie, Dieter Chichung, Moore, Lynne, Nakashima, Kinichi +2 more·2009·Nature Neuroscience
DOI 10.1038/nn.2360PMC PMC2764260
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Abstract

In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.

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  • NEUROD1 and CACNA1G are specific target genes of Wnt/β-catenin signaling in the central nervous system.

    “NEUROD1 and CACNA1G are specific target genes of Wnt/β-catenin signaling in the central nervous system (CNS) [54, 55].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [54]

    The Abstract and Results section on the Neurod1 promoter show that NeuroD1 transcription in adult neural stem cells depends on canonical Wnt/β-catenin signaling. The passages do not identify CACNA1G as a target gene, so this source supports only the NEUROD1 part of the sentence. (LLM, conf=0.87)

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  • Wnt target NEUROD1 is important for adult neurogenesis and the survival and maturation of adult-born neurons.

    “Wnt target NEUROD1 is important for adult neurogenesis and the survival and maturation of adult-born neurons [54, 64].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [54]

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Research works printed but not linked: 40

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Authors
Kuwabara, T., Hsieh, J., Muotri, A., Yeo, G., Warashina, M., Lie, D. C., Moore, L., Nakashima, K., Asashima, M., & Gage, F. H.
Affiliations
  • National Institute of Advanced Industrial Science and Technology (JP)
  • The University of Texas Southwestern Medical Center (US)
  • University of California San Diego (US)
  • Helmholtz Munich (DE)
  • Salk Institute for Biological Studies (US)
  • Nara Institute of Science and Technology (JP)
Corresponding author
Kuwabara, Tomoko
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2009-08-23
Volume
12
Issue
9
Pages
1097-1105
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2360
PMC
PMC2764260
OpenAlex
W2041534255
Cited by
648
References
2
Citations by year
2026: 11 · 2025: 34 · 2024: 21 · 2023: 27 · 2022: 33 · 2021: 46 · 2020: 45 · 2019: 30 · 2018: 43 · 2017: 46 · 2016: 31 · 2015: 38 · 2014: 43 · 2013: 58 · 2012: 56
FWCI
14.85
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • Site cant be reached (submittedVersion)
Funders
  • National Institute of Advanced Industrial Science and Technology
  • National Science Council
  • National Institutes of Health
  • National Institute of Mental Health (MH082070, R56MH082070)
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
adult neurogenesis, Wnt/β-catenin signaling, NeuroD1, β-catenin, TCF/LEF, SOX2, LINE-1 retrotransposons, long interspersed nuclear elements, neural stem cells, neuronal precursors, hippocampus, transcriptional regulation, bidirectional promoter, neuronal differentiation
MeSH terms
Animals, Cell Survival, Cells, Cultured, Female, Hippocampus, Mice, Transgenic, Neurons, Rats, Sprague-Dawley, Mice, Knockout, Long Interspersed Nucleotide Elements, Wnt Proteins, beta Catenin, Mice, Rats, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, TCF Transcription Factors, Adult Stem Cells, Neurogenesis, SOXB1 Transcription Factors, Wnt3 Protein

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