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Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling

Nature Genetics volume 32, pages 594–605 (2002)Cite this article

A Corrigendum to this article was published on 01 January 2003

Abstract

The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound β-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of β-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 β-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in β-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/β-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues.

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Figure 1: Expression analysis of truncated Apc proteins in mutant ES-cell lines.
Figure 2: In vivo differentiation analysis of teratomas derived from wildtype and mutant ES cells.
Figure 3: Analysis of chimeric teratomas showed the cell-autonomous nature of the differentiation defect of ES cells with mutations in Apc.
Figure 4: In vitro differentiation analysis of ApcMin and Apc1638N ES cells.
Figure 5: Biochemical and immunohistochemical analysis of teratomas with mutations in Catnb.
Figure 6: Expression profiling analysis of teratomas with mutations in Apc.

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Acknowledgements

We thank J. Boer and collaborators from the Leiden Genome Technology Center for their assistance with the Affymetrix equipment and G.J.B. van Ommen for his continued support. This study was made possible by a grant to R.F. from the Dutch Research Council. M.R. was supported by grants from the Academy of Finland and the Finnish Cultural Foundation.

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Author notes

  1. Maaret Rindapää and Claudia Gaspar: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Human and Clinical Genetics, Leiden University Medical Center, Sylvius Laboratory, Wassenaarseweg 72, Leiden, 2333 RA, The Netherlands

    Menno F. Kielman, Maaret Rindapää, Claudia Gaspar, Nicole van Poppel, Cor Breukel, Sandra van Leeuwen, Ron Smits & Riccardo Fodde

  2. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Makoto Mark Taketo

  3. Rosetta Inpharmatics, Kirkland, Washington, USA

    Scott Roberts

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  1. Menno F. Kielman
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Correspondence to Riccardo Fodde.

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Kielman, M., Rindapää, M., Gaspar, C. et al. Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling. Nat Genet 32, 594–605 (2002). https://doi.org/10.1038/ng1045

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