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Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways

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Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit+ erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. These precursors developed into CD45+ c-kitlo CX3CR1 immature (A1) cells and matured into CD45+ c-kit CX3CR1+ (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia.

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Figure 1: Identification and characterization of the microglia progenitor.
Figure 2: Characterization of maternal and yolk sac macrophages during development.
Figure 3: Regulation and function of chemokine receptors during microgliogenesis.
Figure 4: MMPs regulate early microglia expansion.
Figure 5: Irf8 and Pu.1 are required for the development of microglia.
Figure 6: Yolk sac precursors depend on the presence of Irf8 and Pu.1.

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  • 06 February 2013

    In the version of this article initially published online, a portion of the affiliation for author Bruno Luckow was given as Medizinische Poliklinik-Klinik und Poliklinik IV. The correct name is Medizinische Klinik und Poliklinik IV. The error has been corrected for the print, PDF and HTML versions of this article.


  1. Hanisch, U.K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387–1394 (2007).

    Article  CAS  Google Scholar 

  2. Ransohoff, R.M. & Perry, V.H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145 (2009).

    Article  CAS  Google Scholar 

  3. Prinz, M., Priller, J., Sisodia, S.S. & Ransohoff, R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  Google Scholar 

  4. Prinz, M. & Mildner, A. Microglia in the CNS: immigrants from another world. Glia 59, 177–187 (2011).

    Article  Google Scholar 

  5. Chan, W.Y., Kohsaka, S. & Rezaie, P. The origin and cell lineage of microglia: new concepts. Brain Res. Rev. 53, 344–354 (2007).

    Article  CAS  Google Scholar 

  6. Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999).

    Article  CAS  Google Scholar 

  7. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  CAS  Google Scholar 

  8. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    Article  CAS  Google Scholar 

  9. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  Google Scholar 

  10. Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

    Article  CAS  Google Scholar 

  11. Takahashi, K., Naito, M. & Takeya, M. Development and heterogeneity of macrophages and their related cells through their differentiation pathways. Pathol. Int. 46, 473–485 (1996).

    Article  CAS  Google Scholar 

  12. Palis, J., Robertson, S., Kennedy, M., Wall, C. & Keller, G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126, 5073–5084 (1999).

    CAS  Google Scholar 

  13. Palis, J. et al. Spatial and temporal emergence of high proliferative potential hematopoietic precursors during murine embryogenesis. Proc. Natl. Acad. Sci. USA 98, 4528–4533 (2001).

    Article  CAS  Google Scholar 

  14. Bertrand, J.Y. et al. Three pathways to mature macrophages in the early mouse yolk sac. Blood 106, 3004–3011 (2005).

    Article  CAS  Google Scholar 

  15. Vinet, J. et al. Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J. Neuroinflammation 9, 27 (2012).

    Article  CAS  Google Scholar 

  16. Wegiel, J. et al. Reduced number and altered morphology of microglial cells in colony stimulating factor-1–deficient osteopetrotic op/op mice. Brain Res. 804, 135–139 (1998).

    Article  CAS  Google Scholar 

  17. Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat. Immunol. 10, 734–743 (2009).

    Article  CAS  Google Scholar 

  18. Hu, J., Van den Steen, P.E., Sang, Q.X. & Opdenakker, G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Discov. 6, 480–498 (2007).

    Article  CAS  Google Scholar 

  19. Hu, J. et al. Inhibition of lethal endotoxin shock with an L-pyridylalanine containing metalloproteinase inhibitor selected by high-throughput screening of a new peptide library. Comb. Chem. High Throughput Screen. 9, 599–611 (2006).

    Article  CAS  Google Scholar 

  20. Rosenbauer, F. & Tenen, D.G. Transcription factors in myeloid development: balancing differentiation with transformation. Nat. Rev. Immunol. 7, 105–117 (2007).

    Article  CAS  Google Scholar 

  21. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  Google Scholar 

  22. Bakri, Y. et al. Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate. Blood 105, 2707–2716 (2005).

    Article  CAS  Google Scholar 

  23. Anderson, K.L. et al. Transcription factor PU.1 is necessary for development of thymic and myeloid progenitor–derived dendritic cells. J. Immunol. 164, 1855–1861 (2000).

    Article  CAS  Google Scholar 

  24. Serbina, N.V. & Pamer, E.G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    Article  CAS  Google Scholar 

  25. Mizutani, M. et al. The fractalkine receptor, but not CCR2, is present on microglia from embryonic development throughout adulthood. J. Immunol. 188, 29–36 (2012).

    Article  CAS  Google Scholar 

  26. McKercher, S.R. et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 15, 5647–5658 (1996).

    Article  CAS  Google Scholar 

  27. Beers, D.R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021–16026 (2006).

    Article  CAS  Google Scholar 

  28. Herbomel, P., Thisse, B. & Thisse, C. Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina and epidermis through a M-CSF receptor–dependent invasive process. Dev. Biol. 238, 274–288 (2001).

    Article  CAS  Google Scholar 

  29. Hambleton, S. et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 365, 127–138 (2011).

    Article  CAS  Google Scholar 

  30. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).

    Article  CAS  Google Scholar 

  31. Mildner, A. et al. Microglia in the adult brain arise from Ly-6C(hi)CCR2(+) monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).

    Article  CAS  Google Scholar 

  32. Mildner, A. et al. Distinct and nonredundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159–11171 (2011).

    Article  CAS  Google Scholar 

  33. 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  Google Scholar 

  34. Raasch, J. et al. I{kappa}B kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-{kappa}B in the central nervous system. Brain 134, 1184–1198 (2011).

    Article  Google Scholar 

  35. Dann, A. et al. Cytosolic RIG-I–like helicases act as negative regulators of sterile inflammation in the CNS. Nat. Neurosci. 15, 98–106 (2012).

    Article  CAS  Google Scholar 

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We would like to thank M. Oberle, A. Hölscher and U. Müller for excellent technical assistance, M. Mann for help with the heat map, A. Müller for assistance with the electron microscopy and S. Brendecke for critical reading and editing. The authors are indebted to S. McKercher (Sanford-Burnham Medical Research Institute) for providing Sfpi+/− mice and to J. Frampton (University of Birmingham) for providing Myb+/− mice. We thank S. Heck and the Flow facility of the Biomedical Research Centre at King's Health Partners. M.P., K.B. and F.R. are supported by the Deutsche Forschungsgemeinschaft (DFG)-funded research unit 1336 “From monocytes to brain macrophages-conditions influencing the fate of myeloid cells in the brain”. M.P. is supported by the Bundesministerium für Bildung und Forschung-funded Competence Network of Multiple Sclerosis (Kompetenznetz Multiple Sklerose), the Competence Network of Neurodegenerative Disorders (Deutsches Zentrum für Neurodegenerative Erkrankungen), the Centre of Chronic Immunodeficiency and the DFG (SFB 620, PR 577/8-1). G.F. is supported by a Heisenberg fellowship (DFG FR 1488/3-2). M.H. is supported by the Helmholtz-Zentrum München, a European Research Council starting grant and the Swiss National Foundation. G.O. is supported by the Geconcentreerde OnderzoeksActies 2012/017 and the Fund for Scientific Research-Flanders. C.S. is supported by a fellowship program of the German National Academy of Sciences Leopoldina (LPDS 2009-31). F.G. is supported by grants MRCG0900867 from the Medical Research Council and ERC-2010-StG-261299 from the European Research Council.

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Kierdorf, K., Erny, D., Goldmann, T. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16, 273–280 (2013).

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