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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.


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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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Correspondence to Marco Prinz.

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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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