Skip to main content

Thank you for visiting 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:

Regulation of progenitor cell proliferation and granulocyte function by microRNA-223


MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes1,2. Despite this prominence, there is a dearth of functional knowledge regarding individual mammalian microRNAs. Using a loss-of-function allele in mice, we report here that the myeloid-specific microRNA-223 (miR-223) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 (also called Mirn223) mutant mice have an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. We show that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR-223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR-223 null mice. In addition, granulocytes lacking miR-223 are hypermature, hypersensitive to activating stimuli and display increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR-223 mutant mice spontaneously develop inflammatory lung pathology and exhibit exaggerated tissue destruction after endotoxin challenge. Our data support a model in which miR-223 acts as a fine-tuner of granulocyte production and the inflammatory response.

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

Access options

Buy this article

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

Figure 1: Phenotypic characterization of miR-223 -/Y mice.
Figure 2: Regulation of progenitor cell proliferation by miR-223.
Figure 3: Mef2c is a functional miR-223 target in myeloid progenitors.
Figure 4: Regulation of neutrophil activity and inflammation by miR-223.

Similar content being viewed by others


  1. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    Article  CAS  Google Scholar 

  2. Taganov, K. D., Boldin, M. P. & Baltimore, D. MicroRNAs and immunity: tiny players in a big field. Immunity 26, 133–137 (2007)

    Article  CAS  Google Scholar 

  3. Lim, L. P., Glasner, M. E., Yekta, S., Burge, C. B. & Bartel, D. P. Vertebrate microRNA genes. Science 299, 1540 (2003)

    Article  CAS  Google Scholar 

  4. Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004)

    Article  CAS  ADS  Google Scholar 

  5. Fazi, F. et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis. Cell 123, 819–831 (2005)

    Article  CAS  Google Scholar 

  6. Fukao, T. et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 129, 617–631 (2007)

    Article  CAS  Google Scholar 

  7. Bohinjec, J. Myelokathexis: chronic neutropenia with hyperplastic bone marrow and hypersegmented neutrophils in two siblings. Blut 42, 191–196 (1981)

    Article  CAS  Google Scholar 

  8. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005)

    Article  CAS  Google Scholar 

  9. Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006)

    Article  CAS  ADS  Google Scholar 

  10. Jackson, R. J. & Standart, N. How do microRNAs regulate gene expression? Sci. STKE 2007, re1 (2007)

    Article  Google Scholar 

  11. Vong, L. H., Ragusa, M. J. & Schwarz, J. J. Generation of conditional Mef2cloxP/loxP mice for temporal- and tissue-specific analyses. Genesis 43, 43–48 (2005)

    Article  CAS  Google Scholar 

  12. Ernst, M. et al. Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. J. Exp. Med. 196, 589–604 (2002)

    Article  CAS  Google Scholar 

  13. Yu, C. C. et al. B and T cells are not required for the viable motheaten phenotype. J. Exp. Med. 183, 371–380 (1996)

    Article  CAS  Google Scholar 

  14. Bjerknes, R. & Aarskog, D. Priming of human polymorphonuclear neutrophilic leukocytes by insulin-like growth factor I: increased phagocytic capacity, complement receptor expression, degranulation, and oxidative burst. J. Clin. Endocrinol. Metab. 80, 1948–1955 (1995)

    CAS  PubMed  Google Scholar 

  15. Fu, Y. K., Arkins, S., Wang, B. S. & Kelley, K. W. A novel role of growth hormone and insulin-like growth factor-I. Priming neutrophils for superoxide anion secretion. J. Immunol. 146, 1602–1608 (1991)

    CAS  PubMed  Google Scholar 

  16. Inoue, T. et al. Growth hormone and insulin-like growth factor I augment bactericidal capacity of human polymorphonuclear neutrophils. Shock 10, 278–284 (1998)

    Article  CAS  Google Scholar 

  17. Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007)

    Article  CAS  Google Scholar 

  18. Voncken, J. W. et al. Increased neutrophil respiratory burst in bcr-null mutants. Cell 80, 719–728 (1995)

    Article  CAS  Google Scholar 

  19. Smith, J. A. Neutrophils, host defense, and inflammation: a double-edged sword. J. Leukoc. Biol. 56, 672–686 (1994)

    Article  CAS  Google Scholar 

  20. Malech, H. L. & Gallin, J. I. Current concepts: immunology. Neutrophils in human diseases. N. Engl. J. Med. 317, 687–694 (1987)

    Article  CAS  Google Scholar 

  21. Eggan, K. et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl Acad. Sci. USA 98, 6209–6214 (2001)

    Article  CAS  ADS  Google Scholar 

  22. Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999)

    Article  CAS  Google Scholar 

  23. Camargo, F. D., Green, R., Capetenaki, Y., Jackson, K. A. & Goodell, M. A. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nature Med. 9, 1520–1527 (2003)

    Article  CAS  Google Scholar 

  24. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000)

    Article  CAS  ADS  Google Scholar 

  25. Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997)

    Article  CAS  Google Scholar 

  26. Rothe, G., Emmendorffer, A., Oser, A., Roesler, J. & Valet, G. Flow cytometric measurement of the respiratory burst activity of phagocytes using dihydrorhodamine 123. J. Immunol. Methods 138, 133–135 (1991)

    Article  CAS  Google Scholar 

Download references


We thank D. Bartel and M. Goodell for critical reading of the manuscript, and members of the Bartel and Jaenisch laboratories for discussions. We also thank H. Mulhern, D. Campagna and S. Gokhale for assistance with morphological analysis, and D. Kombe for mouse handling. We are grateful to J. Schwarz for the gift of Mef2c mutant mice. This work was supported by grants from the Whitehead Institute Fellows program.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Fernando D. Camargo.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S10 with Legends. The Supplementary Figures support the general conclusion that miR-223 fine-tunes the process of granulocyte production and activation. (PDF 1190 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnnidis, J., Harris, M., Wheeler, R. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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.


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