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Notch signals control the fate of immature progenitor cells in the intestine

Nature volume 435, pages 964–968 (2005)Cite this article

Abstract

The Notch signalling pathway plays a crucial role in specifying cellular fates in metazoan development by regulating communication between adjacent cells1,2. Correlative studies suggested an involvement of Notch in intestinal development. Here, by modulating Notch activity in the mouse intestine, we directly implicate Notch signals in intestinal cell lineage specification. We also show that Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. We conclude that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium.

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Figure 1: Activation of Notch signalling induces apoptosis and impairs goblet and enteroendocrine cell differentiation.
Figure 2: Notch activation upregulates Hes-1 and represses the transcription of Math1 and ngn3.
Figure 3: Activation of Notch expands the population of proliferating intestinal progenitors.
Figure 4: Apical defect in Rosa-Notch/Cre + intestinal epithelial cells.

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References

  1. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999)

    Article  ADS  CAS  Google Scholar 

  2. Greenwald, I. LIN-12/Notch signaling: lessons from worms and flies. Genes Dev. 12, 1751–1762 (1998)

    Article  CAS  Google Scholar 

  3. Kimble, J. & Simpson, P. The LIN-12/Notch signaling pathway and its regulation. Annu. Rev. Cell Dev. Biol. 13, 333–361 (1997)

    Article  CAS  Google Scholar 

  4. Weinmaster, G. The ins and outs of notch signaling. Mol. Cell. Neurosci. 9, 91–102 (1997)

    Article  CAS  Google Scholar 

  5. Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Varnum-Finney, B. et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nature Med. 6, 1278–1281 (2000)

    Article  CAS  Google Scholar 

  7. Jensen, J. et al. Control of endodermal endocrine development by Hes-1. Nature Genet. 24, 36–44 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Yang, Q., Bermingham, N. A., Finegold, M. J. & Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158 (2001)

    Article  ADS  CAS  Google Scholar 

  9. Jenny, M. et al. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21, 6338–6347 (2002)

    Article  CAS  Google Scholar 

  10. Pinto, D., Robine, S., Jaisser, F., El Marjou, F. E. & Louvard, D. Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines. J. Biol. Chem. 274, 6476–6482 (1999)

    Article  CAS  Google Scholar 

  11. Madison, B. B. et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002)

    Article  CAS  Google Scholar 

  12. Maunoury, R. et al. Developmental regulation of villin gene expression in the epithelial cell lineages of mouse digestive and urogenital tracts. Development 115, 717–728 (1992)

    CAS  Google Scholar 

  13. Maunoury, R. et al. Villin expression in the visceral endoderm and in the gut anlage during early mouse embryogenesis. EMBO J. 7, 3321–3329 (1988)

    Article  CAS  Google Scholar 

  14. el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004)

    Article  CAS  Google Scholar 

  15. Murtaugh, L. C., Stanger, B. Z., Kwan, K. M. & Melton, D. A. Notch signaling controls multiple steps of pancreatic differentiation. Proc. Natl Acad. Sci. USA 100, 14920–14925 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Hofer, D. & Drenckhahn, D. Cytoskeletal markers allowing discrimination between brush cells and other epithelial cells of the gut including enteroendocrine cells. Histochem. Cell Biol. 105, 405–412 (1996)

    Article  CAS  Google Scholar 

  17. Bry, L. et al. Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc. Natl Acad. Sci. USA 91, 10335–10339 (1994)

    Article  ADS  CAS  Google Scholar 

  18. Ohtsuka, T. et al. Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation. EMBO J. 18, 2196–2207 (1999)

    Article  CAS  Google Scholar 

  19. Zine, A. & de Ribaupierre, F. Notch/Notch ligands and Math1 expression patterns in the organ of Corti of wild-type and Hes1 and Hes5 mutant mice. Hear. Res. 170, 22–31 (2002)

    Article  CAS  Google Scholar 

  20. Lee, J. C. et al. Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes 50, 928–936 (2001)

    Article  CAS  Google Scholar 

  21. Go, M. J., Eastman, D. S. & Artavanis-Tsakonas, S. Cell proliferation control by Notch signaling in Drosophila development. Development 125, 2031–2040 (1998)

    CAS  Google Scholar 

  22. Capobianco, A. J., Zagouras, P., Blaumueller, C. M., Artavanis-Tsakonas, S. & Bishop, J. M. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol. Cell. Biol. 17, 6265–6273 (1997)

    Article  CAS  Google Scholar 

  23. Gerdes, J., Schwab, U., Lemke, H. & Stein, H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int. J. Cancer 31, 13–20 (1983)

    Article  CAS  Google Scholar 

  24. Fath, K. R., Obenauf, S. D. & Burgess, D. R. Cytoskeletal protein and mRNA accumulation during brush border formation in adult chicken enterocytes. Development 109, 449–459 (1990)

    CAS  Google Scholar 

  25. Louvard, D., Kedinger, M. & Hauri, H. P. The differentiating intestinal epithelial cell: establishment and maintenance of functions through interactions between cellular structures. Annu. Rev. Cell Biol. 8, 157–195 (1992)

    Article  CAS  Google Scholar 

  26. van Es, J. et al. Notch pathway/γ-secretase inhibition turns proliferative cells in intestinal crypts and neoplasia into Goblet cells. Nature doi:10.1038/nature03659 (this issue)

  27. Crosnier, C. et al. Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine. Development 132, 1093–1094 (2005)

    Article  CAS  Google Scholar 

  28. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998)

    Article  CAS  Google Scholar 

  29. Galceran, J., Sustmann, C., Hsu, S. C., Folberth, S. & Grosschedl, R. LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis. Genes Dev. 18, 2718–2723 (2004)

    Article  CAS  Google Scholar 

  30. Sancho, E., Batlle, E. & Clevers, H. Live and let die in the intestinal epithelium. Curr. Opin. Cell Biol. 15, 763–770 (2003)

    Article  CAS  Google Scholar 

  31. Ito, T. et al. Basic helix–loop–helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium. Development 127, 3913–3921 (2000)

    CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Isselbacher, A. McClatchey, M. Curto and I. Saotome for technical help, discussions and critical reading of the manuscript. S.A.-T. was supported by the National Institutes of Health. S.R. and D.L. were supported by the Association pour la Recherche sur le Cancer and Biologie du développement et physiologie intégrative.

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Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, 02129, USA

    Silvia Fre, Philippos Mourikis & Spyros Artavanis-Tsakonas

  2. Morphogenesis and Intracellular Signaling, Institut Curie-CNRS, 75248, Paris, France

    Silvia Fre, Mathilde Huyghe, Sylvie Robine & Daniel Louvard

  3. Faculté des Sciences d'Orsay, Université de Paris-Sud XI, 91405, Orsay, France

    Philippos Mourikis

  4. Collège de France, 75231, Paris, France

    Spyros Artavanis-Tsakonas

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  1. Silvia Fre
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Correspondence to Spyros Artavanis-Tsakonas.

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Supplementary information

Supplementary Figure S1

Cre-mediated over-expression of activated Notch. (PDF 94 kb)

Supplementary Figure S2

Disruption of the rostro-caudal wave of intestinal differentiation elicited by Notch activation during embryonic development. (PDF 115 kb)

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Fre, S., Huyghe, M., Mourikis, P. et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968 (2005). https://doi.org/10.1038/nature03589

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