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Cited by 84Pluripotent Stem Cells ResearchWnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene Regulation

Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation

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Atlasi, Yaser, Noori, Rubina, Gaspar, Claudia, Franken, Patrick, Sacchetti, Andrea, Rafati, Haleh, Mahmoudi, Tokameh, Decraene, Charles +3 more·2013·PLoS Genetics
DOI 10.1371/journal.pgen.1003424PMC PMC3642041
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Abstract

Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic stem cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gene constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and endodermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage differentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expression profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that down-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restored the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 down-regulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells.

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  • These studies showed that abnormal catenin regulation induced dysregulated in vitro differentiation (and not proliferation), findings in keeping with the APC heterozygous human iPSC line.

    “These studies showed that abnormal catenin regulation induced dysregulated in vitro differentiation (and not proliferation), findings in keeping with our APC heterozygous human iPSC line.”

    From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [35]

    The Results section (pages not provided) reports that constitutive Wnt signaling prevented differentiation in a short-term in vitro assay and that Apc-mutant mouse ESCs showed defective neural differentiation in vitro. It does not establish the claim’s “and not proliferation” distinction; the Results also report that very high Wnt signaling could compromise colony formation and growth. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A limited number of reports describe APC mutant lines, all done on mouse ESC expressing either hypomorphic mutant variants of APC or specifically overexpressing β-catenin APC mutations.

    “This is supported by the existence of a limited number of reports describing APC mutant lines, which were all done on mouse ESC expressing either hypomorphic mutant variants of APC [35] or specifically overexpressing β-catenin APC mutations [36].”

    From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [35]

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Authors
Atlasi, Y., Noori, R., Gaspar, C., Franken, P., Sacchetti, A., Rafati, H., Mahmoudi, T., Decraene, C., Calin, G. A., Merrill, B. J., & Fodde, R.
Affiliations
  • Erasmus MC (NL)
  • Centre National de la Recherche Scientifique (FR)
  • University of Illinois Chicago (US)
Corresponding author
Fodde, Riccardo
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2013-05-02
Volume
9
Issue
5
Pages
e1003424
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1003424
PMC
PMC3642041
OpenAlex
W2133656012
Cited by
84
References
4
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 9 · 2020: 8 · 2019: 4 · 2018: 9 · 2017: 14 · 2016: 5 · 2015: 9 · 2014: 10 · 2013: 1
FWCI
3.74
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Laura and John Arnold Foundation
  • National Institutes of Health
  • University of Texas MD Anderson Cancer Center
  • National Cancer Institute (R01CA128571)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • 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
Wnt signaling, mouse embryonic stem cells, TCF3, APC mutation, neuronal differentiation, lineage differentiation, histone modifications, H3K4me3, histone H3 acetylation, miR-211, post-transcriptional regulation, pluripotency, self-renewal
MeSH terms
Animals, Cell Differentiation, Mutation, Transcription, Genetic, Down-Regulation, Gene Expression Regulation, Developmental, Cell Lineage, DNA Methylation, Adenomatous Polyposis Coli Protein, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Embryonic Stem Cells, Wnt Signaling Pathway

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