title: Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways.
abstract: 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-kit(lo) CX(3)CR1(-) immature (A1) cells and matured into CD45(+) c-kit(-) CX(3)CR1(+) (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.
authors: Department of Neuropathology, University of Freiburg, Freiburg, Germany.
authors: Katrin
authors: K
authors: Kierdorf
authors: Daniel
authors: D
authors: Erny
authors: Tobias
authors: T
authors: Goldmann
authors: Victor
authors: V
authors: Sander
authors: Christian
authors: C
authors: Schulz
authors: Elisa Gomez
authors: EG
authors: Perdiguero
authors: Peter
authors: P
authors: Wieghofer
authors: Annette
authors: A
authors: Heinrich
authors: Pia
authors: P
authors: Riemke
authors: Christoph
authors: C
authors: Hölscher
authors: Dominik N
authors: DN
authors: Müller
authors: Bruno
authors: B
authors: Luckow
authors: Thomas
authors: T
authors: Brocker
authors: Katharina
authors: K
authors: Debowski
authors: Günter
authors: G
authors: Fritz
authors: Ghislain
authors: G
authors: Opdenakker
authors: Andreas
authors: A
authors: Diefenbach
authors: Knut
authors: K
authors: Biber
authors: Mathias
authors: M
authors: Heikenwalder
authors: Frederic
authors: F
authors: Geissmann
authors: Frank
authors: F
authors: Rosenbauer
authors: Marco
authors: M
authors: Prinz
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050835:Interferon Regulatory Factors; D000090062:Kruppel-Like Factor 4; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; C000715468:Klf4 protein, mouse