Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling
Abstract
The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and tumorigenesis in the adult organism. The adenomatous polyposis coli gene (APC) is a major controller of the Wnt pathway and is essential to prevent tumorigenesis in a variety of tissues and organs. Here, we have investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Catnb also affects the differentiation potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supports the differentiation defects at the molecular level and pinpoints a large number of downstream structural and regulating genes. Chimeric experiments showed that this effect is cell-autonomous. Our results imply that constitutive activation of the Apc/beta-catenin sig…
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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 [36]
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 [36]
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Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells
Sommer, C. A., Capilla, A., Molina-Estevez, F. J., Gianotti-Sommer, A., Skvir, N., Caballero, I., Chowdhury, S., & Mostoslavsky, G. (2018) · PLOS ONE · doi:10.1371/journal.pone.0200657 · Cited by 39 · see citing works
“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].”
Background
- Authors
- Kielman, M. F., Rindapää, M., Gaspar, C., van Poppel, N., Breukel, C., van Leeuwen, S., Taketo, M. M., Roberts, S., Smits, R., & Fodde, R.
- Affiliations
- Leiden University Medical Center (NL)
- Kyoto University (JP)
- Corresponding author
- Fodde, Riccardo
- Venue
- Nature Genetics
- Published
- 2002-11-11
- Volume
- 32
- Issue
- 4
- Pages
- 594-605
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2066307520
- Cited by
- 362
- References
- 2
- Citations by year
- 2026: 5 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 11 · 2019: 13 · 2018: 10 · 2017: 13 · 2016: 11 · 2015: 17 · 2014: 13 · 2013: 19 · 2012: 22
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Topics
- 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 › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- APC, β-catenin signaling, Wnt signaling, embryonic stem cell differentiation, three germ layers, APC mutation, teratoma, carcinogenesis, colon cancer, tissue homeostasis, chimeric mice
- MeSH terms
- Alleles, Animals, Cell Differentiation, Cell Line, Cells, Cultured, Cytoskeletal Proteins, Embryo, Mammalian, Genotype, Heterozygote, Homozygote, Mice, Inbred C57BL, Mice, Inbred Strains, Teratoma, Transplantation, Isogeneic, Signal Transduction, Trans-Activators, Genes, APC, Germ-Line Mutation, Gene Dosage, Gene Expression Profiling, Adenomatous Polyposis Coli Protein, Pluripotent Stem Cells, beta Catenin, Mice
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