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Notch signalling controls pancreatic cell differentiation

Nature volume 400, pages 877–881 (1999)Cite this article

Abstract

The pancreas contains both exocrine and endocrine cells, but the molecular mechanisms controlling the differentiation of these cell types are largely unknown. Despite their endodermal origin, pancreatic endocrine cells share several molecular characteristics with neurons1,2,3,4,5, and, like neurons in the central nervous system6,7, differentiating endocrine cells in the pancreas appear in a scattered fashion within a field of progenitor cells8,9. This indicates that they may be generated by lateral specification through Notch signalling6,7. Here, to test this idea, we analysed pancreas development in mice genetically altered at several steps in the Notch signalling pathway. Mice deficient for Delta-like gene 1 (Dll1)10 or the intracellular mediator RBP-Jκ11 showed accelerated differentiation of pancreatic endocrine cells. A similar phenotype was observed in mice over-expressing neurogenin 3(ngn 3)12 or the intracellular form of Notch3 (ref. 13) (a repressor of Notch signalling). These data provide evidence that ngn3 acts as pro-endocrine gene and that Notch signalling is critical for the decision between theendocrine and progenitor/exocrine fates in the developing pancreas.

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Figure 1: ngn3 is expressed and functions as a pro-endocrine gene during pancreatic development.
Figure 2: Notch signalling components are expressed in the developing pancreas.
Figure 3: Lack of RBP-Jκ and Dll1 leads to precocious pancreatic endocrine differentiation.
Figure 4: Repressed Notch signalling obstructs pancreatic epithelial branching and exocrine differentiation.

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Acknowledgements

We thank K. Falk, U. B. Backman, U. Valtersson and I. Berglund for technical assistance; T. Edlund for critical reading and comments; and members of our laboratories for helpful discussions. This work was supported by grants from the Swedish Medical Research Council and the Juvenile Diabetes Foundation, New York (to H.E.)

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Author notes

  1. Åsa Apelqvist, Hao Li and Martin Hrabě de Angelis: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Microbiology, University of Umeå, S-901 87, Umeå, Sweden

    Åsa Apelqvist, Hao Li & Helena Edlund

  2. Institute of Cell Biology, Swiss Federal Institute of Technology, ETH-Hoenggerberg HPM E38, CH-8093, Zürich, Switzerland

    Lukas Sommer

  3. Division of Biology 216-76, California Institute of Technology, 1201 E. California Blvd., Pasadena, 91125, California, USA

    David J. Anderson

  4. Department of Medical Chemistry, Kyoto University Faculty of Medicine, Sakyo-ku Yoshida, 6068501, Kyoto, Japan

    Tasuku Honjo

  5. GSF, Institute for Mammalian Genetics, Ingolstaedter Landstrasse 1, D-85764, Neuherberg, Germany

    Martin Hrabě de Angelis

  6. Department of Cell and Molecular Biology, Karolinska Institute, S-171 77, Stockholm, Sweden

    Paul Beatus & Urban Lendahl

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Correspondence to Helena Edlund.

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Apelqvist, Å., Li, H., Sommer, L. et al. Notch signalling controls pancreatic cell differentiation. Nature 400, 877–881 (1999). https://doi.org/10.1038/23716

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