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.

  • Letter
  • Published:

Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation

Nature volume 461, pages 537–541 (2009)Cite this article

Abstract

Reactive oxygen species (ROS), produced during various electron transfer reactions in vivo, are generally considered to be deleterious to cells1. In the mammalian haematopoietic system, haematopoietic stem cells contain low levels of ROS. However, unexpectedly, the common myeloid progenitors (CMPs) produce significantly increased levels of ROS2. The functional significance of this difference in ROS level in the two progenitor types remains unresolved2,3. Here we show that Drosophila multipotent haematopoietic progenitors, which are largely akin to the mammalian myeloid progenitors4, display increased levels of ROS under in vivo physiological conditions, which are downregulated on differentiation. Scavenging the ROS from these haematopoietic progenitors by using in vivo genetic tools retards their differentiation into mature blood cells. Conversely, increasing the haematopoietic progenitor ROS beyond their basal level triggers precocious differentiation into all three mature blood cell types found in Drosophila, through a signalling pathway that involves JNK and FoxO activation as well as Polycomb downregulation. We conclude that the developmentally regulated, moderately high ROS level in the progenitor population sensitizes them to differentiation, and establishes a signalling role for ROS in the regulation of haematopoietic cell fate. Our results lead to a model that could be extended to reveal a probable signalling role for ROS in the differentiation of CMPs in mammalian haematopoietic development and oxidative stress response.

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: ROS profile of third-instar lymph glands.
Figure 2: Increased ROS production triggers precocious differentiation of the multipotent progenitors.
Figure 3: Disrupting JNK signalling suppresses the ROS-dependent differentiation phenotype.
Figure 4: FoxO activation and Polycomb downregulation phenocopy aspects of the ROS-induced differentiation.

Similar content being viewed by others

References

  1. Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007)

    Article  CAS  Google Scholar 

  3. Coffer, P. J. & Burgering, B. M. Stressed marrow: FoxOs stem tumour growth. Nature Cell Biol. 9, 251–253 (2007)

    Article  CAS  Google Scholar 

  4. Evans, C. J., Hartenstein, V. & Banerjee, U. Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoiesis. Dev. Cell 5, 673–690 (2003)

    Article  CAS  Google Scholar 

  5. Jung, S. H., Evans, C. J., Uemura, C. & Banerjee, U. The Drosophila lymph gland as a developmental model of hematopoiesis. Development 132, 2521–2533 (2005)

    Article  CAS  Google Scholar 

  6. Wood, W. & Jacinto, A. Drosophila melanogaster embryonic haemocytes: masters of multitasking. Nature Rev. Mol. Cell Biol. 8, 542–551 (2007)

    Article  CAS  Google Scholar 

  7. Lebestky, T., Jung, S. H. & Banerjee, U. A. Serrate-expressing signaling center controls Drosophila hematopoiesis. Genes Dev. 17, 348–353 (2003)

    Article  CAS  Google Scholar 

  8. Mandal, L., Martinez-Agosto, J. A., Evans, C. J., Hartenstein, V. & Banerjee, U. A. Hedgehog- and Antennapedia-dependent niche maintains Drosophila haematopoietic precursors. Nature 446, 320–324 (2007)

    Article  ADS  CAS  Google Scholar 

  9. Krzemien, J. et al. Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre. Nature 446, 325–328 (2007)

    Article  ADS  CAS  Google Scholar 

  10. Lebestky, T., Chang, T., Hartenstein, V. & Banerjee, U. Specification of Drosophila hematopoietic lineage by conserved transcription factors. Science 288, 146–149 (2000)

    Article  ADS  CAS  Google Scholar 

  11. Bruckner, K. et al. The PDGF/VEGF receptor controls blood cell survival in Drosophila . Dev. Cell 7, 73–84 (2004)

    Article  Google Scholar 

  12. Missirlis, F. et al. A putative glutathione peroxidase of Drosophila encodes a thioredoxin peroxidase that provides resistance against oxidative stress but fails to complement a lack of catalase activity. Biol. Chem. 384, 463–472 (2003)

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Owusu-Ansah, E., Yavari, A., Mandal, S. & Banerjee, U. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nature Genet. 40, 356–361 (2008)

    Article  CAS  Google Scholar 

  15. Owusu-Ansah, E., Yavari, A. . & Banerjee, U. . A protocol for in vivo detection of reactive oxygen species. Nature Protocols 10.1038/nprot.2008.23 (2008)

  16. Gotoh, Y. & Cooper, J. A. Reactive oxygen species- and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-α signal transduction. J. Biol. Chem. 273, 17477–17482 (1998)

    Article  CAS  Google Scholar 

  17. Essers, M. A. et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23, 4802–4812 (2004)

    Article  CAS  Google Scholar 

  18. Martin-Blanco, E. et al. puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila . Genes Dev. 12, 557–570 (1998)

    Article  CAS  Google Scholar 

  19. Harvey, K. F. et al. FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. J. Cell Biol. 180, 691–696 (2008)

    Article  CAS  Google Scholar 

  20. Wang, M. C., Bohmann, D. & Jasper, H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121, 115–125 (2005)

    Article  CAS  Google Scholar 

  21. Lee, N., Maurange, C., Ringrose, L. & Paro, R. Suppression of Polycomb group proteins by JNK signalling induces transdetermination in Drosophila imaginal discs. Nature 438, 234–237 (2005)

    Article  ADS  CAS  Google Scholar 

  22. Puig, O., Marr, M. T., Ruhf, M. L. & Tjian, R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev. 17, 2006–2020 (2003)

    Article  CAS  Google Scholar 

  23. Teleman, A. A., Hietakangas, V., Sayadian, A. C. & Cohen, S. M. Nutritional control of protein biosynthetic capacity by insulin via Myc in Drosophila . Cell Metab. 7, 21–32 (2008)

    Article  CAS  Google Scholar 

  24. Junger, M. A. et al. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J. Biol. 2, 20 (2003)

    Article  Google Scholar 

  25. Takeda, S. et al. Local positive feedback regulation determines cell shape in root hair cells. Science 319, 1241–1244 (2008)

    Article  ADS  CAS  Google Scholar 

  26. Foreman, J. et al. Reactive oxygen species produced by NADPH oxidase regulate plant cell growth. Nature 422, 442–446 (2003)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank I. Ando and H. Muller for antibodies, and E. Hafen, A. Martinez-Arias, F. Missirlis, S. Noselli, R. Paro, S Sinenko, the National Institute of Genetics Fly Stock Center (Japan) and the Bloomington Stock Center for fly stocks. We acknowledge M. Kulkarni and C. Pitsouli of the Perrimon laboratory for technical assistance. Owing to space limitations, we apologize to our colleagues whose work is not referenced. This study was supported by US National Institutes of Health grant R01HL067395 to U.B. and a T32 institutional postdoctoral fellowship T32-HL069766 to E.O.-A.

Author Contributions U.B. supervised the project. E.O.-A. conceived, designed and performed all experiments. E.O.-A. and U.B. discussed results and wrote the manuscript.

Author information

Author notes

  1. Edward Owusu-Ansah

    Present address: Present address: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.,

Authors and Affiliations

  1. Department of Molecular, Cell and Developmental Biology,

    Edward Owusu-Ansah & Utpal Banerjee

  2. Molecular Biology Institute,,

    Utpal Banerjee

  3. Department of Biological Chemistry,,

    Utpal Banerjee

  4. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA ,

    Utpal Banerjee

Authors
  1. Edward Owusu-Ansah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Utpal Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Utpal Banerjee.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S6 and Supplementary Table 1. (PDF 7364 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Owusu-Ansah, E., Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009). https://doi.org/10.1038/nature08313

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08313

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