Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells

Abstract

In the Drosophila midgut, multipotent intestinal stem cells (ISCs) that are scattered along the epithelial basement membrane maintain tissue homeostasis by their ability to steadily produce daughters that differentiate into either enterocytes or enteroendocrine cells, depending on the levels of Notch activity1,2,3. However, the mechanisms controlling ISC self-renewal remain elusive. Here we show that a canonical Wnt signalling pathway controls ISC self-renewal. The ligand Wingless (Wg) is specifically expressed in the circular muscles next to ISCs, separated by a thin layer of basement membrane. Reduced function of wg causes ISC quiescence and differentiation, whereas wg overexpression produces excessive ISC-like cells that express high levels of the Notch ligand, Delta. Clonal analysis shows that the main downstream components of the Wg pathway, including Frizzled, Dishevelled and Armadillo, are autonomously required for ISC self-renewal. Furthermore, epistatic analysis suggests that Notch acts downstream of the Wg pathway and a hierarchy of Wg/Notch signalling pathways controls the balance between self-renewal and differentiation of ISCs. These data suggest that the underlying circular muscle constitutes the ISC niche, which produce Wg signals that act directly on ISCs to promote ISC self-renewal. This study demonstrates markedly conserved mechanisms regulating ISCs from Drosophila to mammals. The identification of the Drosophila ISC niche and the principal self-renewal signal will facilitate further understanding of intestinal homeostasis control and tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: wg is specifically expressed in the circular muscles.
Figure 2: wg is necessary and sufficient for ISC self-renewal.
Figure 3: Canonical wg signalling pathway components function cell-autonomously for ISC self-renewal.
Figure 4: Functional relationships between Wg and Notch signalling in regulating ISCs.

References

  1. Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006)

    Article  ADS  CAS  Google Scholar 

  2. Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Ohlstein, B. & Spradling, A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315, 988–992 (2007)

    Article  ADS  CAS  Google Scholar 

  4. Crosnier, C., Stamataki, D. & Lewis, J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nature Rev. Genet. 7, 349–359 (2006)

    Article  CAS  Google Scholar 

  5. Kassis, J. A., Noll, E., VanSickle, E. P., Odenwald, W. F. & Perrimon, N. Altering the insertional specificity of a Drosophila transposable element. Proc. Natl Acad. Sci. USA 89, 1919–1923 (1992)

    Article  ADS  CAS  Google Scholar 

  6. Bejsovec, A. & Martinez Arias, A. Roles of wingless in patterning the larval epidermis of Drosophila . Development 113, 471–485 (1991)

    CAS  PubMed  Google Scholar 

  7. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993)

    CAS  PubMed  Google Scholar 

  8. Moon, R. T., Bowerman, B., Boutros, M. & Perrimon, N. The promise and perils of Wnt signaling through β-catenin. Science 296, 1644–1646 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Lee, T., Winter, C., Marticke, S. S., Lee, A. & Luo, L. Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis. Neuron 25, 307–316 (2000)

    Article  CAS  Google Scholar 

  10. Chen, C. M. & Struhl, G. Wingless transduction by the Frizzled and Frizzled2 proteins of Drosophila . Development 126, 5441–5452 (1999)

    CAS  PubMed  Google Scholar 

  11. Bhanot, P. et al. Frizzled and Dfrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development. Development 126, 4175–4186 (1999)

    CAS  PubMed  Google Scholar 

  12. Heslip, T. R., Theisen, H., Walker, H. & Marsh, J. L. Shaggy and dishevelled exert opposite effects on Wingless and Decapentaplegic expression and on positional identity in imaginal discs. Development 124, 1069–1078 (1997)

    CAS  PubMed  Google Scholar 

  13. Peifer, M. & Wieschaus, E. The segment polarity gene armadillo encodes a functionally modular protein that is the Drosophila homolog of human plakoglobin. Cell 63, 1167–1176 (1990)

    Article  CAS  Google Scholar 

  14. Song, X. & Xie, T. wingless signaling regulates the maintenance of ovarian somatic stem cells in Drosophila . Development 130, 3259–3268 (2003)

    Article  CAS  Google Scholar 

  15. Pai, L. M., Orsulic, S., Bejsovec, A. & Peifer, M. Negative regulation of Armadillo, a Wingless effector in Drosophila . Development 124, 2255–2266 (1997)

    CAS  PubMed  Google Scholar 

  16. Struhl, G. & Basler, K. Organizing activity of wingless protein in Drosophila . Cell 72, 527–540 (1993)

    Article  CAS  Google Scholar 

  17. van de Wetering, M. et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF . Cell 88, 789–799 (1997)

    Article  CAS  Google Scholar 

  18. Bourouis, M. Targeted increase in shaggy activity levels blocks wingless signaling. Genesis 34, 99–102 (2002)

    Article  CAS  Google Scholar 

  19. Ohlstein, B., Kai, T., Decotto, E. & Spradling, A. The stem cell niche: theme and variations. Curr. Opin. Cell Biol. 16, 693–699 (2004)

    Article  CAS  Google Scholar 

  20. Nystul, T. & Spradling, A. An epithelial niche in the Drosophila ovary undergoes long-range stem cell replacement. Cell Stem Cell 1, 277–285 (2007)

    Article  CAS  Google Scholar 

  21. Nikolova, G., Strilic, B. & Lammert, E. The vascular niche and its basement membrane. Trends Cell Biol. 17, 19–25 (2007)

    Article  CAS  Google Scholar 

  22. Gregorieff, A. et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005)

    Article  CAS  Google Scholar 

  23. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5 . Nature 449, 1003–1007 (2007)

    Article  ADS  CAS  Google Scholar 

  24. Radtke, F. & Clevers, H. Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909 (2005)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Struhl, L. Cooley, S. Hayashi, T. Xie, the Bloomington Stock Center for fly stocks, and members of the Xi laboratory for comments and discussions. This work was supported by an ‘863’ grant 2007AA02Z1A2 to R.X. from the Chinese Ministry of Science and Technology.

Author Contributions G.L. and R.X. designed the research; N.X. performed the in situ hybridization experiments and G.L. performed all other experiments; G.L., N.X. and R.X. analysed the data and R.X. wrote the paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rongwen Xi.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, G., Xu, N. & Xi, R. Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature 455, 1119–1123 (2008). https://doi.org/10.1038/nature07329

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07329

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing