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Hedgehog acts as a somatic stem cell factor in the Drosophila ovary

Abstract

Secreted signalling molecules of the Hedgehog (Hh) family have many essential patterning roles during development of diverse organisms including Drosophila and humans1,2. Although Hedgehog proteins most commonly affect cell fate, they can also stimulate cell proliferation. In humans several distinctive cancers, including basal-cell carcinoma, result from mutations that aberrantly activate Hh signal transduction3. In Drosophila, Hh directly stimulates proliferation of ovarian somatic cells4,5,6. Here we show that Hh acts specifically on stem cells in the Drosophila ovary. These cells cannot proliferate as stem cells in the absence of Hh signalling, whereas excessive Hh signalling produces supernumerary stem cells. We deduce that Hh is a stem-cell factor and suggest that human cancers due to excessive Hh signalling might result from aberrant expansion of stem cell pools.

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Figure 1: The Drosophila germarium.
Figure 2: Phospho-histone H3 labelling of follicle cells and somatic stem cells.
Figure 3: Counting somatic stem cells in wild-type and ptc mutant ovarioles.
Figure 4: Direct labelling of wild-type and ptc mutant somatic stem cells.
Figure 5: Somatic stem cell proliferation requires smo and ci activities.

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References

  1. Ingham, P. W. Transducing Hedgehog: the story so far. EMBO J. 17, 3505–3511 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ruiz i Altaba, A. Gli proteins and Hedgehog signaling. Trends Genet. 15, 418–425 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Wicking, C., Smyth, I. & Bale, A. The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18, 7844–7851 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Forbes, A. J., Lin, H., Ingham, P. W. & Spradling, A. C. Hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. Development 122, 1125–1135 (1996).

    CAS  PubMed  Google Scholar 

  5. Forbes, A. J., Spradling, A. C., Ingham, P. W. & Lin, H. The role of segment polarity genes during early oogenesis in Drosophila. Development 122, 3283–3294 (1996).

    CAS  PubMed  Google Scholar 

  6. Zhang, Y. & Kalderon, D. Regulation of cell proliferation and patterning in Drosophila oogenesis by Hedgehog signaling. Development 127, 2165–2176 (2000).

    CAS  PubMed  Google Scholar 

  7. Spradling, A. C. Developmental genetics of oogenesis. In The Development of Drosophila melanogaster (eds Bate, M. & Martinez-Arias, A.) 1–70 (Cold Spring Harbor Lab., Cold Spring Harbor, New York, 1993).

    Google Scholar 

  8. Margolis, J. & Spradling, A. C. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 121, 3797–3807 (1995).

    CAS  PubMed  Google Scholar 

  9. Hendzel, M. J. et al. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106, 348–360 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Xu, T. & Rubin, G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993).

    CAS  PubMed  Google Scholar 

  11. Spradling, A. C. et al. The Drosophila germarium: stem cells, germ line cysts and oocytes. Cold Spring Harbor Symp. Quant. Biol. 62, 25–34 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Harrison, D. & Perrimon, N. A simple and efficient method for generation of marked clones in Drosophila. Curr. Biol. 3, 424–433 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Price, M. A. & Kalderon, D. Proteolysis of Cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. Development 126, 4331–4339 (1999).

    CAS  PubMed  Google Scholar 

  14. Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Xie, J. et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Dahmane, N., Lee, J., Robins, P., Heller, P. & Ruiz i Altaba, A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876–881 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Gailani, M. R. et al. The role of the human homolog of Drosophila patched in sporadic basal-cell carcinomas. Nature Genet. 14, 78–81 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal-cell nevus syndrome. Science 272, 1668–1671 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Fan, H. R., Oro, A. E., Scott, M. P. & Khavari, P. A. Induction of basal-cell carcinoma features in transgenic human skin expressing sonic hedgehog. Nature Med. 3, 788–792 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Nilsson, M. et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc. Natl Acad. Sci. USA 97, 3438–3443 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oro, A. E. et al. Basal cell carcinomas in mice overexpressing Sonic hedgehog. Science 276, 817–821 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Hardy, M. H. The secret life of the hair follicle. Trends Genet. 8, 55–61 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Rochat, A., Kobayashi, K. & Barrandon, Y. Location of stem cells of human hair follicles by clonal analysis. Cell 76, 1063–1073 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Taylor, G., Lehner, M. S., Jensen, P. J., Sun, T. -T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Kruger, K., Blume-Peytavi, U. & Orfanos, C. E. Basal cell carcinoma possibly originates from the outer root sheath and/or the bulge region of the vellus hair follicle. Arch. Dermatol. Res. 291, 253–259 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  30. 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 

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Acknowledgements

We thank D. Harrison, J. Jiang, N. Methot, N. Patel and A. Spradling for reagents; J. Briscoe for help with confocal microscopy; D. Rabinowitz for statistical modelling of stem cell behaviour; J. Erickson, J. Mohler, M. A. Price and R. Lavker for critical discussions. This work was supported by an NIH grant to D.K.

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Correspondence to Daniel Kalderon.

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Zhang, Y., Kalderon, D. Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature 410, 599–604 (2001). https://doi.org/10.1038/35069099

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