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.

A self-organizing system of repressor gradients establishes segmental complexity in Drosophila

Nature volume 426, pages 849–853 (2003)Cite this article

Abstract

Gradients of regulatory factors are essential for establishing precise patterns of gene expression during development1,2,3; however, it is not clear how patterning information in multiple gradients is integrated to generate complex body plans. Here we show that opposing gradients of two Drosophila transcriptional repressors, Hunchback (Hb) and Knirps (Kni), position several segments by differentially repressing two distinct regulatory regions (enhancers) of the pair-rule gene even-skipped (eve). Computational and in vivo analyses suggest that enhancer sensitivity to repression is controlled by the number and affinity of repressor-binding sites. Because the kni expression domain is positioned between two gradients of Hb, each enhancer directs expression of a pair of symmetrical stripes, one on each side of the kni domain. Thus, only two enhancers are required for the precise positioning of eight stripe borders (four stripes), or more than half of the whole eve pattern. Our results show that complex developmental expression patterns can be generated by simple repressor gradients. They also support the utility of computational analyses for defining and deciphering regulatory information contained in genomic DNA.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Individual eve stripes are differentially responsive to gradients of Kni and Hb.
Figure 2: Clusters of repressor-binding sites determine enhancer sensitivity.
Figure 3: Mutual repression between Hb and Kni.
Figure 4: Repressor gradients and the generation of pattern complexity.

References

  1. Driever, W., Thoma, G. & Nusslein-Volhard, C. Determination of spatial domains of zygotic gene expression in the Drosophila embryo by the affinity of binding sites for the bicoid morphogen. Nature 340, 363–367 (1989)

    Article  ADS  CAS  Google Scholar 

  2. Struhl, G., Johnston, P. & Lawrence, P. A. Control of Drosophila body pattern by the hunchback morphogen gradient. Cell 69, 237–249 (1992)

    Article  CAS  Google Scholar 

  3. Jiang, J. & Levine, M. Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen. Cell 72, 741–752 (1993)

    Article  CAS  Google Scholar 

  4. Goto, T., Macdonald, P. & Maniatis, T. Early and late periodic patterns of even skipped expression are controlled by distinct regulatory elements that respond to different spatial cues. Cell 57, 413–422 (1989)

    Article  CAS  Google Scholar 

  5. Harding, K., Hoey, T., Warrior, R. & Levine, M. Autoregulatory and gap gene response elements of the even-skipped promoter of Drosophila. EMBO J. 8, 1205–1212 (1989)

    Article  CAS  Google Scholar 

  6. Fujioka, M., Emi-Sarker, Y., Yusibova, G. L., Goto, T. & Jaynes, J. B. Analysis of an even-skipped rescue transgene reveals both composite and discrete neuronal and early blastoderm enhancers, and multi-stripe positioning by gap gene repressor gradients. Development 126, 2527–2538 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Small, S., Blair, A. & Levine, M. Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 11, 4047–4057 (1992)

    Article  CAS  Google Scholar 

  8. Small, S., Blair, A. & Levine, M. Regulation of two pair-rule stripes by a single enhancer in the Drosophila embryo. Dev. Biol. 175, 314–324 (1996)

    Article  CAS  Google Scholar 

  9. Small, S., Kraut, R., Hoey, T., Warrior, R. & Levine, M. Transcriptional regulation of a pair-rule stripe in Drosophila. Genes Dev. 5, 827–839 (1991)

    Article  CAS  Google Scholar 

  10. Stanojevic, D., Small, S. & Levine, M. Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo. Science 254, 1385–1387 (1991)

    Article  ADS  CAS  Google Scholar 

  11. Stanojevic, D., Hoey, T. & Levine, M. Sequence-specific DNA-binding activities of the gap proteins encoded by hunchback and Kruppel in Drosophila. Nature 341, 331–335 (1989)

    Article  ADS  CAS  Google Scholar 

  12. Yan, R., Small, S., Desplan, C., Dearolf, C. R. & Darnell, J. E. Jr Identification of a Stat gene that functions in Drosophila development. Cell 84, 421–430 (1996)

    Article  CAS  Google Scholar 

  13. Hou, X. S., Melnick, M. B. & Perrimon, N. Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell 84, 411–419 (1996); erratum ibid. Cell 85, 290 (1996)

    Article  CAS  Google Scholar 

  14. Nambu, P. A. & Nambu, J. R. The Drosophila fish-hook gene encodes a HMG domain protein essential for segmentation and CNS development. Development 122, 3467–3475 (1996)

    CAS  PubMed  Google Scholar 

  15. Ip, Y. T., Park, R. E., Kosman, D., Yazdanbakhsh, K. & Levine, M. dorsal–twist interactions establish snail expression in the presumptive mesoderm of the Drosophila embryo. Genes Dev. 6, 1518–1530 (1992)

    Article  CAS  Google Scholar 

  16. Papatsenko, D. A. et al. Extraction of functional binding sites from unique regulatory regions: the Drosophila early developmental enhancers. Genome Res. 12, 470–481 (2002)

    Article  CAS  Google Scholar 

  17. Lifanov, A. P., Makeev, V. J., Nazina, A. G. & Papatsenko, D. A. Homotypic regulatory clusters in Drosophila. Genome Res. 13, 579–588 (2003)

    Article  CAS  Google Scholar 

  18. Berman, B. P. et al. Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc. Natl Acad. Sci. USA 99, 757–762 (2002)

    Article  ADS  CAS  Google Scholar 

  19. Kosman, D. & Small, S. Concentration-dependent patterning by an ectopic expression domain of the Drosophila gap gene knirps. Development 124, 1343–1354 (1997)

    CAS  PubMed  Google Scholar 

  20. Hulskamp, M., Pfeifle, C. & Tautz, D. A morphogenetic gradient of hunchback protein organizes the expression of the gap genes Kruppel and knirps in the early Drosophila embryo. Nature 346, 577–580 (1990)

    Article  ADS  CAS  Google Scholar 

  21. Kraut, R. & Levine, M. Mutually repressive interactions between the gap genes giant and Kruppel define middle body regions of the Drosophila embryo. Development 111, 611–621 (1991)

    CAS  PubMed  Google Scholar 

  22. Struhl, G., Struhl, K. & Macdonald, P. M. The gradient morphogen bicoid is a concentration-dependent transcriptional activator. Cell 57, 1259–1273 (1989)

    Article  CAS  Google Scholar 

  23. Driever, W. & Nusslein-Volhard, C. The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner. Cell 54, 95–104 (1988)

    Article  CAS  Google Scholar 

  24. Langeland, J. A., Attai, S. F., Vorwerk, K. & Carroll, S. B. Positioning adjacent pair-rule stripes in the posterior Drosophila embryo. Development 120, 2945–2955 (1994)

    CAS  PubMed  Google Scholar 

  25. Hanna-Rose, W. & Hansen, U. Active repression mechanisms of eukaryotic transcription repressors. Trends Genet. 12, 229–234 (1996)

    Article  CAS  Google Scholar 

  26. Gray, S. & Levine, M. Transcriptional repression in development. Curr. Opin. Cell Biol. 8, 358–364 (1996)

    Article  CAS  Google Scholar 

  27. Andrioli, L. P., Vasisht, V., Theodosopoulou, E., Oberstein, A. & Small, S. Anterior repression of a Drosophila stripe enhancer requires three position-specific mechanisms. Development 129, 4931–4940 (2002)

    CAS  PubMed  Google Scholar 

  28. Small, S. In vivo analysis of lacZ fusion genes in transgenic Drosophila melanogaster. Methods Enzymol. 326, 146–159 (2000)

    Article  CAS  Google Scholar 

  29. Struhl, G., Fitzgerald, K. & Greenwald, I. Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell 74, 331–345 (1993)

    Article  CAS  Google Scholar 

  30. Lawrence, P. A., Johnston, P., Macdonald, P. & Struhl, G. Borders of parasegments in Drosophila embryos are delimited by the fushi tarazu and even-skipped genes. Nature 328, 440–442 (1987)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Fujioka and J. Jaynes for transgenic flies containing the eve 4 + 6–lacZ construct; L. Andrioli for discussions and support; A. Oberstein for technical assistance; and C. Desplan, J. Blau and T. Cook for encouragement and comments on the manuscript. D.E.C. was supported by a grant from the NSF. This work was also supported by a grant from the NIH.

Author information

Author notes

  1. Dorothy E. Clyde

    Present address: Biosciences Department, University of Kent, Canterbury, CT2 7NJ, UK

  2. Xuelin Wu

    Present address: Plant Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, 92037, USA

  3. Dorothy E. Clyde and Maria S. G. Corado: These authors contributed equally to this work

Authors and Affiliations

  1. Biology Department, New York University, New York, New York, 10003, USA

    Dorothy E. Clyde, Maria S. G. Corado, Adam Paré, Dmitri Papatsenko & Stephen Small

Authors
  1. Dorothy E. Clyde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria S. G. Corado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuelin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adam Paré
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dmitri Papatsenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephen Small
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen Small.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Clyde, D., Corado, M., Wu, X. et al. A self-organizing system of repressor gradients establishes segmental complexity in Drosophila. Nature 426, 849–853 (2003). https://doi.org/10.1038/nature02189

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02189

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