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The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling


The intestinal tract maintains proper function by replacing aged cells with freshly produced cells that arise from a population of self-renewing intestinal stem cells (ISCs). In the mammalian intestine, ISC self renewal, amplification and differentiation take place along the crypt–villus axis, and are controlled by the Wnt and hedgehog (Hh) signalling pathways1. However, little is known about the mechanisms that specify ISCs within the developing intestinal epithelium, or about the signalling centres that help maintain them in their self-renewing stem cell state. Here we show that in adult Drosophila melanogaster, ISCs of the posterior intestine (hindgut) are confined to an anterior narrow segment, which we name the hindgut proliferation zone (HPZ). Within the HPZ, self renewal of ISCs, as well as subsequent proliferation and differentiation of ISC descendants, are controlled by locally emanating Wingless (Wg, a Drosophila Wnt homologue) and Hh signals. The anteriorly restricted expression of Wg in the HPZ acts as a niche signal that maintains cells in a slow-cycling, self-renewing mode. As cells divide and move posteriorly away from the Wg source, they enter a phase of rapid proliferation. During this phase, Hh signal is required for exiting the cell cycle and the onset of differentiation. The HPZ, with its characteristic proliferation dynamics and signalling properties, is set up during the embryonic phase and becomes active in the larva, where it generates all adult hindgut cells including ISCs. The mechanism and genetic control of cell renewal in the Drosophila HPZ exhibits a large degree of similarity with what is seen in the mammalian intestine. Our analysis of the Drosophila HPZ provides an insight into the specification and control of stem cells, highlighting the way in which the spatial pattern of signals that promote self renewal, growth and differentiation is set up within a genetically tractable model system.

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Figure 1: Proliferating cells of the Drosophila hindgut are confined to a morphologically and molecularly defined zone (HPZ).
Figure 2: The HPZ is formed in the embryo and produces the adult hindgut during the larval and pupal phases.
Figure 3: Wg signalling promotes proliferation and maintenance of the hindgut stem cell population.
Figure 4: The Hh signal promotes differentiation of the Drosophila hindgut epithelium.

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  1. 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  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 24, 251–254 (2001)

    Article  CAS  PubMed  Google Scholar 

  5. Bach, E. A. et al. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo . Gene Expr. Patterns 7, 323–331 (2007)

    Article  CAS  PubMed  Google Scholar 

  6. Murakami, R., Takashima, S. & Hamaguchi, T. Developmental genetics of the Drosophila gut: specification of primordia, subdivision and overt-differentiation. Cell. Mol. Biol. 45, 661–676 (1999)

    CAS  PubMed  Google Scholar 

  7. Lengyel, J. A. & Iwaki, D. D. It takes guts: the Drosophila hindgut as a model system for organogenesis. Dev. Biol. 243, 1–19 (2002)

    Article  CAS  PubMed  Google Scholar 

  8. Smith, A. V. & Orr-Weaver, T. L. The regulation of the cell cycle during Drosophila embryogenesis: the transition to polyteny. Development 112, 997–1008 (1991)

    CAS  PubMed  Google Scholar 

  9. Robertson, C. W. The metamorphosis of Drosophila melanogaster, including an accurately timed account of the principal morphological changes. J. Morphol. 59, 351–399 (1936)

    Article  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kuhnert, F. et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl Acad. Sci. USA 101, 266–271 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. van den Brink, G. R. et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nature Genet. 36, 277–282 (2004)

    Article  CAS  PubMed  Google Scholar 

  14. Madison, B. B. et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 132, 279–289 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. McGuire, S. E., Le, P. T., Osborn, A. J., Matsumoto, K. & Davis, R. L. Spatiotemporal rescue of memory dysfunction in Drosophila . Science 302, 1765–1768 (2003)

    Article  ADS  CAS  PubMed  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  PubMed  Google Scholar 

  18. Methot, N. & Basler, K. Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 96, 819–831 (1999)

    Article  CAS  PubMed  Google Scholar 

  19. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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We thank DSHB, NIG-Fly and Bloomington stock center for flies and antibodies. We also thank all members of the Hartenstein laboratory and Merriam laboratory for discussions. This work was supported by an NIH grant to J.R.M. and V.H.

Author Contributions S.T., J.R.M. and V.H. designed the project. The experiments were carried out by S.T., M.M. and A.Y.-H.

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Correspondence to Volker Hartenstein.

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Takashima, S., Mkrtchyan, M., Younossi-Hartenstein, A. et al. The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling. Nature 454, 651–655 (2008).

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