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.

  • Article
  • Published:

Type IV collagens regulate BMP signalling in Drosophila

Nature volume 455, pages 72–77 (2008)Cite this article

Abstract

Dorsal–ventral patterning in vertebrate and invertebrate embryos is mediated by a conserved system of secreted proteins that establishes a bone morphogenetic protein (BMP) gradient. Although the Drosophila embryonic Decapentaplegic (Dpp) gradient has served as a model to understand how morphogen gradients are established, no role for the extracellular matrix has been previously described. Here we show that type IV collagen extracellular matrix proteins bind Dpp and regulate its signalling in both the Drosophila embryo and ovary. We provide evidence that the interaction between Dpp and type IV collagen augments Dpp signalling in the embryo by promoting gradient formation, yet it restricts the signalling range in the ovary through sequestration of the Dpp ligand. Together, these results identify a critical function of type IV collagens in modulating Dpp in the extracellular space during Drosophila development. On the basis of our findings that human type IV collagen binds BMP4, we predict that this role of type IV collagens will be conserved.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Dpp binds to type IV collagens.
Figure 2: Type IV collagen distribution in the embryo and germarium.
Figure 3: Type IV collagens increase Dpp signalling in the embryo.
Figure 4: Collagen IV increases GSC number.
Figure 5: Mechanistic insight into the function of Dpp–collagen-IV interactions in the embryo.

Similar content being viewed by others

References

  1. Hogan, B. L. Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev. 6, 432–438 (1996)

    Article  CAS  Google Scholar 

  2. Kishigami, S. & Mishina, Y. BMP signaling and early embryonic patterning. Cytokine Growth Factor Rev. 16, 265–278 (2005)

    Article  CAS  Google Scholar 

  3. Chen, D., Zhao, M. & Mundy, G. R. Bone morphogenetic proteins. Growth Factors 22, 233–241 (2004)

    Article  CAS  Google Scholar 

  4. Bobik, A. Transforming growth factor-βs and vascular disorders. Arterioscler. Thromb. Vasc. Biol. 26, 1712–1720 (2006)

    Article  CAS  Google Scholar 

  5. Harradine, K. A. & Akhurst, R. J. Mutations of TGFβ signaling molecules in human disease. Ann. Med. 38, 403–414 (2006)

    Article  CAS  Google Scholar 

  6. Reddi, A. H. BMPs: from bone morphogenetic proteins to body morphogenetic proteins. Cytokine Growth Factor Rev. 16, 249–250 (2005)

    Article  CAS  Google Scholar 

  7. Bessa, P. C., Casal, M. & Reis, R. L. Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J. Tissue Eng. Regen. Med. 2, 81–96 (2008)

    Article  CAS  Google Scholar 

  8. Podos, S. D. & Ferguson, E. L. Morphogen gradients: new insights from DPP. Trends Genet. 15, 396–402 (1999)

    Article  CAS  Google Scholar 

  9. Ashe, H. L. BMP signalling: synergy and feedback create a step gradient. Curr. Biol. 15, R375–R377 (2005)

    Article  CAS  Google Scholar 

  10. Kirilly, D. & Xie, T. The Drosophila ovary: an active stem cell community. Cell Res. 17, 15–25 (2007)

    Article  CAS  Google Scholar 

  11. Eldar, A. et al. Robustness of the BMP morphogen gradient in Drosophila embryonic patterning. Nature 419, 304–308 (2002)

    Article  ADS  CAS  Google Scholar 

  12. Shimmi, O., Umulis, D., Othmer, H. & O’Connor, M. B. Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo. Cell 120, 873–886 (2005)

    Article  CAS  Google Scholar 

  13. Wang, Y. C. & Ferguson, E. L. Spatial bistability of Dpp-receptor interactions during Drosophila dorsal–ventral patterning. Nature 434, 229–234 (2005)

    Article  ADS  CAS  Google Scholar 

  14. Khoshnoodi, J., Cartailler, J. P., Alvares, K., Veis, A. & Hudson, B. G. Molecular recognition in the assembly of collagens: terminal noncollagenous domains are key recognition modules in the formation of triple helical protomers. J. Biol. Chem. 281, 38117–38121 (2006)

    Article  CAS  Google Scholar 

  15. Yasothornsrikul, S., Davis, W. J., Cramer, G., Kimbrell, D. A. & Dearolf, C. R. viking: identification and characterization of a second type IV collagen in Drosophila . Gene 198, 17–25 (1997)

    Article  CAS  Google Scholar 

  16. Blumberg, B., MacKrell, A. J. & Fessler, J. H. Drosophila basement membrane procollagen α1(IV). Complete cDNA sequence, genomic structure, and general implications for supramolecular assemblies. J. Biol. Chem. 263, 18328–18337 (1988)

    CAS  PubMed  Google Scholar 

  17. Ross, J. J. et al. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410, 479–483 (2001)

    Article  ADS  CAS  Google Scholar 

  18. Knibiehler, B., Mirre, C. & Le Parco, Y. Collagen type IV of Drosophila is stockpiled in the growing oocyte and differentially located during early stages of embryogenesis. Cell Differ. Dev. 30, 147–157 (1990)

    Article  CAS  Google Scholar 

  19. Medioni, C. & Noselli, S. Dynamics of the basement membrane in invasive epithelial clusters in Drosophila . Development 132, 3069–3077 (2005)

    Article  CAS  Google Scholar 

  20. Morin, X., Daneman, R., Zavortink, M. & Chia, W. A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila . Proc. Natl Acad. Sci. USA 98, 15050–15055 (2001)

    Article  ADS  CAS  Google Scholar 

  21. Bhat, M. A. et al. Discs Lost, a novel multi-PDZ domain protein, establishes and maintains epithelial polarity. Cell 96, 833–845 (1999)

    Article  CAS  Google Scholar 

  22. Lunstrum, G. P. et al. Drosophila basement membrane procollagen IV. J. Biol. Chem. 263, 18318–18327 (1988)

    CAS  PubMed  Google Scholar 

  23. Ashe, H. L., Mannervik, M. & Levine, M. Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo. Development 127, 3305–3312 (2000)

    CAS  PubMed  Google Scholar 

  24. Ashe, H. L. & Levine, M. Local inhibition and long-range enhancement of Dpp signal transduction by Sog. Nature 398, 427–431 (1999)

    Article  ADS  CAS  Google Scholar 

  25. Xie, T. & Spradling, A. C. decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell 94, 251–260 (1998)

    Article  CAS  Google Scholar 

  26. Larrain, J. et al. BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 127, 821–830 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Maduzia, L. L. & Padgett, R. W. Drosophila MAD, a member of the Smad family, translocates to the nucleus upon stimulation of the dpp pathway. Biochem. Biophys. Res. Commun. 238, 595–598 (1997)

    Article  CAS  Google Scholar 

  28. Lee, H. S., Simon, J. A. & Lis, J. T. Structure and expression of ubiquitin genes of Drosophila melanogaster . Mol. Cell. Biol. 8, 4727–4735 (1988)

    Article  CAS  Google Scholar 

  29. Schock, F. & Perrimon, N. Retraction of the Drosophila germ band requires cell–matrix interaction. Genes Dev. 17, 597–602 (2003)

    Article  CAS  Google Scholar 

  30. Reed, B. H., Wilk, R., Schock, F. & Lipshitz, H. D. Integrin-dependent apposition of Drosophila extraembryonic membranes promotes morphogenesis and prevents anoikis. Curr. Biol. 14, 372–380 (2004)

    Article  CAS  Google Scholar 

  31. Belenkaya, T. Y. et al. Drosophila Dpp morphogen movement is independent of dynamin-mediated endocytosis but regulated by the glypican members of heparan sulfate proteoglycans. Cell 119, 231–244 (2004)

    Article  CAS  Google Scholar 

  32. Abe, H. et al. Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J. Biol. Chem. 279, 14201–14206 (2004)

    Article  CAS  Google Scholar 

  33. Paralkar, V. M., Weeks, B. S., Yu, Y. M., Kleinman, H. K. & Reddi, A. H. Recombinant human bone morphogenetic protein 2B stimulates PC12 cell differentiation: potentiation and binding to type IV collagen. J. Cell Biol. 119, 1721–1728 (1992)

    Article  CAS  Google Scholar 

  34. Yu, K. et al. Processing of the Drosophila Sog protein creates a novel BMP inhibitory activity. Development 127, 2143–2154 (2000)

    CAS  PubMed  Google Scholar 

  35. Srinivasan, S., Rashka, K. E. & Bier, E. Creation of a Sog morphogen gradient in the Drosophila embryo. Dev. Cell 2, 91–101 (2002)

    Article  CAS  Google Scholar 

  36. Persson, U. et al. The L45 loop in type I receptors for TGF-β family members is a critical determinant in specifying Smad isoform activation. FEBS Lett. 434, 83–87 (1998)

    Article  CAS  Google Scholar 

  37. McKearin, D. & Ohlstein, B. A role for the Drosophila bag-of-marbles protein in the differentiation of cystoblasts from germline stem cells. Development 121, 2937–2947 (1995)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. O’Connor for plasmids, flies and advice on Dpp–HA staining; W. Chia, R. Ray and the Bloomington stock centre for fly stocks; E. Bier, P. ten Dijke, H. Bellen, L. Fessler and D. McKearin for antibodies; T. Jowitt for help with SPR; S. Lunj, M. Ronshaugen and W. Song for help; M. Ashe and W. Miles for reading the manuscript; and M. Levine whose laboratory this work was initiated in. This work was funded by a BBSRC project grant to H.L.A. and a BBSRC studentship to R.E.H.

Author Contributions H.L.A. designed and obtained funding for the experiments. X.W. generated the in vitro and embryonic data. R.E.H. performed the ovary experiments. L.J.B. provided technical assistance with cloning, fly counts and transgenics. X.W., R.E.H. and H.L.A. analysed and interpreted the data, and H.L.A. wrote the paper.

Author information

Authors and Affiliations

  1. Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK ,

    Xiaomeng Wang, Robin E. Harris, Laura J. Bayston & Hilary L. Ashe

Authors
  1. Xiaomeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin E. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura J. Bayston
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hilary L. Ashe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hilary L. Ashe.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-10 with Legends and additional references The data include further characterisation of the following: collagen IV-Dpp/BMP interaction; collagen IV expression and distribution in the embryo; and phenotype of type IV collagen mutant embryos. (PDF 2500 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, X., Harris, R., Bayston, L. et al. Type IV collagens regulate BMP signalling in Drosophila. Nature 455, 72–77 (2008). https://doi.org/10.1038/nature07214

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07214

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

Advanced 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