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.

Direct sensing of systemic and nutritional signals by haematopoietic progenitors in Drosophila

Nature Cell Biology volume 14, pages 394–400 (2012)Cite this article

Subjects

Abstract

The Drosophila lymph gland is a haematopoietic organ in which progenitor cells, which are most akin to the common myeloid progenitor in mammals, proliferate and differentiate into three types of mature cell—plasmatocytes, crystal cells and lamellocytes—the functions of which are reminiscent of mammalian myeloid cells1. During the first and early second instars of larval development, the lymph gland contains only progenitors, whereas in the third instar, a medial region of the primary lobe of the lymph gland called the medullary zone contains these progenitors2, and maturing blood cells are found juxtaposed in a peripheral region designated the cortical zone2. A third group of cells referred to as the posterior signalling centre functions as a haematopoietic niche3,4. Similarly to mammalian myeloid cells, Drosophila blood cells respond to multiple stresses including hypoxia, infection and oxidative stress5,6,7. However, how systemic signals are sensed by myeloid progenitors to regulate cell-fate determination has not been well described. Here, we show that the haematopoietic progenitors of Drosophila are direct targets of systemic (insulin) and nutritional (essential amino acid) signals, and that these systemic signals maintain the progenitors by promoting Wingless (WNT in mammals) signalling. We expect that this study will promote investigation of such possible direct signal sensing mechanisms by mammalian myeloid progenitors.

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

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Starvation induces abnormal differentiation in the lymph gland.
Figure 2: Starvation induces an inflammatory response in blood cells.
Figure 3: Systemic dilp2 is directly sensed by haematopoietic progenitors.
Figure 4: Systemic essential amino acids (EAAs) are directly sensed by haematopoietic progenitors.
Figure 5: wg as a target of Dilp2–InR–dTOR signalling.

References

  1. Meister, M. Blood cells of Drosophila: cell lineages and role in host defence. Curr. Opin. Immunol. 16, 10–15 (2004).

    Article  CAS  Google Scholar 

  2. 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 

  3. 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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Mukherjee, T., Kim, W. S., Mandal, L. & Banerjee, U. Interaction between Notch and Hif-α in development and survival of Drosophila blood cells. Science 332, 1210–1213 (2011).

    Article  CAS  Google Scholar 

  6. Lemaitre, B. & Hoffmann, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    Article  CAS  Google Scholar 

  7. Owusu-Ansah, E. & Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009).

    Article  CAS  Google Scholar 

  8. Nelson, R. E. et al. Peroxidasin: a novel enzyme-matrix protein of Drosophila development. EMBO J. 13, 3438–3447 (1994).

    Article  CAS  Google Scholar 

  9. Goto, A. et al. A Drosophila haemocyte-specific protein, hemolectin, similar to human von Willebrand factor. Biochem. J. 359, 99–108 (2001).

    Article  CAS  Google Scholar 

  10. Kocks, C. et al. Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila. Cell 123, 335–346 (2005).

    Article  CAS  Google Scholar 

  11. Becker, T. et al. FOXO-dependent regulation of innate immune homeostasis. Nature 463, 369–373 (2010).

    Article  CAS  Google Scholar 

  12. Geminard, C., Rulifson, E. J. & Leopold, P. Remote control of insulin secretion by fat cells in Drosophila. Cell Metab. 10, 199–207 (2009).

    Article  CAS  Google Scholar 

  13. Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    Article  CAS  Google Scholar 

  14. Flores-Saaib, R. D., Jia, S. & Courey, A. J. Activation and repression by the C-terminal domain of Dorsal. Development 128, 1869–1879 (2001).

    CAS  PubMed  Google Scholar 

  15. Tzou, P. et al. Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia. Immunity 13, 737–748 (2000).

    Article  CAS  Google Scholar 

  16. Bidla, G., Dushay, M. S. & Theopold, U. Crystal cell rupture after injury in Drosophila requires the JNK pathway, small GTPases and the TNF homolog Eiger. J. Cell Sci. 120, 1209–1215 (2007).

    Article  CAS  Google Scholar 

  17. Rulifson, E. J., Kim, S. K. & Nusse, R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296, 1118–1120 (2002).

    Article  CAS  Google Scholar 

  18. Ikeya, T., Galic, M., Belawat, P., Nairz, K. & Hafen, E. Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr. Biol. 12, 1293–1300 (2002).

    Article  CAS  Google Scholar 

  19. Zhang, H. et al. Deletion of Drosophila insulin-like peptides causes growth defects and metabolic abnormalities. Proc. Natl Acad. Sci. USA 106, 19617–19622 (2009).

    Article  CAS  Google Scholar 

  20. Ren, D. et al. A prokaryotic voltage-gated sodium channel. Science 294, 2372–2375 (2001).

    Article  CAS  Google Scholar 

  21. Bohni, R. et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97, 865–875 (1999).

    Article  CAS  Google Scholar 

  22. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724 (2000).

    Article  CAS  Google Scholar 

  23. Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5, 566–571 (2003).

    Article  CAS  Google Scholar 

  24. Lee, J. Y. et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell 7, 593–605 (2010).

    Article  CAS  Google Scholar 

  25. Slaidina, M., Delanoue, R., Gronke, S., Partridge, L. & Leopold, P. A Drosophila insulin-like peptide promotes growth during nonfeeding states. Dev. Cell 17, 874–884 (2009).

    Article  CAS  Google Scholar 

  26. Rutter, G. A. Nutrient-secretion coupling in the pancreatic islet β-cell: recent advances. Mol. Aspects Med. 22, 247–284 (2001).

    Article  CAS  Google Scholar 

  27. Colombani, J. et al. A nutrient sensor mechanism controls Drosophila growth. Cell 114, 739–749 (2003).

    Article  CAS  Google Scholar 

  28. Sinenko, S. A., Mandal, L., Martinez-Agosto, J. A. & Banerjee, U. Dual role of wingless signaling in stem-like hematopoietic precursor maintenance in Drosophila. Dev. Cell 16, 756–763 (2009).

    Article  CAS  Google Scholar 

  29. Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).

    Article  CAS  Google Scholar 

  30. Sousa-Nunes, R., Yee, L. L. & Gould, A. P. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 471, 508–512 (2011).

    Article  CAS  Google Scholar 

  31. Chell, J. M. & Brand, A. H. Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell 143, 1161–1173 (2010).

    Article  CAS  Google Scholar 

  32. Choi, N. H., Lucchetta, E. & Ohlstein, B. Nonautonomous regulation of Drosophila midgut stem cell proliferation by the insulin-signaling pathway. Proc. Natl Acad. Sci. USA 108, 18702–18707 (2011).

    Article  CAS  Google Scholar 

  33. Hsu, H. J. & Drummond-Barbosa, D. Insulin levels control female germline stem cell maintenance via the niche in Drosophila. Proc. Natl Acad. Sci. USA 106, 1117–1121 (2009).

    Article  CAS  Google Scholar 

  34. McLeod, C. J., Wang, L., Wong, C. & Jones, D. L. Stem cell dynamics in response to nutrient availability. Curr. Biol. CB 20, 2100–2105 (2010).

    Article  CAS  Google Scholar 

  35. O’Brien, L. E., Soliman, S. S., Li, X. & Bilder, D. Altered modes of stem cell division drive adaptive intestinal growth. Cell 147, 603–614 (2011).

    Article  Google Scholar 

  36. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Zettervall, C. J. et al. A directed screen for genes involved in Drosophila blood cell activation. Proc. Natl Acad. Sci. USA 101, 14192–14197 (2004).

    Article  CAS  Google Scholar 

  39. Hennig, K. M., Colombani, J. & Neufeld, T. P. TOR coordinates bulk and targeted endocytosis in the Drosophila melanogaster fat body to regulate cell growth. J. Cell Biol. 173, 963–974 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. J. Evans, K. T. Jones, other members of the Banerjee laboratory and J. A. Martinez-Agosto for helpful comments and discussions. We thank R. Erdmann for help with the amino-acid supplementation assay and S. Pham for confirming experiments with anti-Hml in different genetic backgrounds. We acknowledge P. Leopold, E. Hafen, E. Rulifson, L. Pick, T. P. Neufeld, R. A. Schulz, A. Courey, J-M. Reichhart, the VDRC Stock Center and the Bloomington Stock Center for fly stocks, the Developmental Studies Hybridoma Bank (University of Iowa), the Drosophila Genomics Resource Center and J. Fessler for reagents. We also thank M. Crozatiers’ group for providing the in situ hybridization protocol. This work was supported by an NIH grant (5R01 HL067395) to U.B. and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Training Grant at UCLA to J.S.

Author information

Authors and Affiliations

  1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California 90095, USA

    Jiwon Shim, Tina Mukherjee & Utpal Banerjee

  2. Molecular Biology Institute, University of California, Los Angeles, California 90095, USA

    Utpal Banerjee

  3. Department of Biological Chemistry, University of California, Los Angeles, California 90095, USA

    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. Jiwon Shim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tina Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Utpal Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S designed and carried out experiments, and U.B. supervised the project. T.M. carried out experiments. J.S., T.M. and U.B. discussed and analysed results and wrote the manuscript.

Corresponding author

Correspondence to Utpal Banerjee.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 761 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shim, J., Mukherjee, T. & Banerjee, U. Direct sensing of systemic and nutritional signals by haematopoietic progenitors in Drosophila. Nat Cell Biol 14, 394–400 (2012). https://doi.org/10.1038/ncb2453

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2453

This article is cited by

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