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Notch1 functions as a tumor suppressor in mouse skin

Nature Genetics volume 33, pages 416–421 (2003)Cite this article

Abstract

Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems1, and aberrant Notch signaling is associated with tumorigenesis2,3,4,5. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin6,7. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1−/− embryos die during gestation8,9,10,11,12. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma–like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed β-catenin signaling in cells that should normally undergo differentiation. Enhanced β-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of β-catenin, indicating that Notch1 can inhibit β-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.

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Figure 1: Hyperplasia of the corneal epithelium induced by inactivation of Notch1 in adult mice.
Figure 2: Formation of skin tumors induced by inactivation of Notch1 in adult mice.
Figure 3: Notch1 deficiency facilitates tumorigenicity.
Figure 4: Upregulation of Shh target genes in spontaneous skin tumors of Notch1−/− mice and induced Notch1−/− keratinocytes.
Figure 5: Notch1 deficiency results in increased β-catenin signaling.

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Acknowledgements

We thank G. Badic, E. Säuberly and J. Bamat for histological analysis; B. Sordat, M. Guitard and F. Sierro for technical help; P. Chambon and D. Metzger for the K5–cre–ERT transgenic mice; and T. Jacks and A. Trumpp for the Cdnk1a−/− mice. This work was supported by grants from the Swiss Cancer League/Oncosuisse (to F.R.), the National Cancer Institute of Canada (to C.C.H.) and the US National Institutes of Health (to G.P.D.).

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Lausanne Branch, University Lausanne, Epalinges, 1066, Switzerland

    Michael Nicolas, Anita Wolfer & Freddy Radtke

  2. Swiss Institute for Experimental Cancer Research, Epalinges, 1066, Switzerland

    Michael Nicolas & Kenneth Raj

  3. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    J. Alain Kummer

  4. The Hospital for Sick Children and Department of Molecular and Medical Genetics, Program in Developmental Biology, University of Toronto, Toronto, Canada

    Pleasantine Mill & Chi-chung Hui

  5. Department of Immunology, Erasmus University Rotterdam/University 3000 DR Rotterdam and Departments of Immunology and Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

    Mascha van Noort & Hans Clevers

  6. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

    G. Paolo Dotto

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  1. Michael Nicolas
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Correspondence to Freddy Radtke.

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Nicolas, M., Wolfer, A., Raj, K. et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33, 416–421 (2003). https://doi.org/10.1038/ng1099

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