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

Katrin Kierdorf; Daniel Erny; Tobias Goldmann; Victor Sander; Christian Schulz; Elisa Gomez Perdiguero; Peter Wieghofer; Annette Heinrich; Pia Riemke; Christoph Hoelscher; Dominik N. Mueller; Bruno Luckow; Thomas Brocker; Katharina Debowski; Guenter Fritz; Ghislain Opdenakker; Andreas Diefenbach; Knut Biber; Mathias Heikenwalder; Frederic Geissmann; Frank Rosenbauer; Marco Prinz

doi:10.1038/nn.3318

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

Katrin Kierdorf, Daniel Erny, Tobias Goldmann, Victor Sander, Christian Schulz, Elisa Gomez Perdiguero, Peter Wieghofer, Annette Heinrich, Pia Riemke, Christoph Hoelscher, Dominik N. Mueller, Bruno Luckow, Thomas Brocker, Katharina Debowski, Guenter Fritz, Ghislain Opdenakker, Andreas Diefenbach, Knut Biber, Mathias Heikenwalder, Frederic GeissmannFrank Rosenbauer, Marco Prinz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1059 Citations (Scopus)

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.

Original language	English
Pages (from-to)	273-280
Number of pages	8
Journal	Nature Neuroscience
Volume	16
Issue number	3
DOIs	https://doi.org/10.1038/nn.3318
Publication status	Published - Mar 2013

Keywords

YOLK-SAC
TRANSCRIPTION FACTORS
FRACTALKINE RECEPTOR
DENDRITIC CELLS
MYELOID CELLS
MACROPHAGES
BRAIN
DIFFERENTIATION
HETEROGENEITY
PROGENITORS

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Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., Wieghofer, P., Heinrich, A., Riemke, P., Hoelscher, C., Mueller, D. N., Luckow, B., Brocker, T., Debowski, K., Fritz, G., Opdenakker, G., Diefenbach, A., Biber, K., Heikenwalder, M., ... Prinz, M. (2013). Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nature Neuroscience, 16(3), 273-280. https://doi.org/10.1038/nn.3318

@article{ab332948ad6e4c2eb1a9eb5112824182,

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.",

keywords = "YOLK-SAC, TRANSCRIPTION FACTORS, FRACTALKINE RECEPTOR, DENDRITIC CELLS, MYELOID CELLS, MACROPHAGES, BRAIN, DIFFERENTIATION, HETEROGENEITY, PROGENITORS",

author = "Katrin Kierdorf and Daniel Erny and Tobias Goldmann and Victor Sander and Christian Schulz and Perdiguero, {Elisa Gomez} and Peter Wieghofer and Annette Heinrich and Pia Riemke and Christoph Hoelscher and Mueller, {Dominik N.} and Bruno Luckow and Thomas Brocker and Katharina Debowski and Guenter Fritz and Ghislain Opdenakker and Andreas Diefenbach and Knut Biber and Mathias Heikenwalder and Frederic Geissmann and Frank Rosenbauer and Marco Prinz",

year = "2013",

month = mar,

doi = "10.1038/nn.3318",

language = "English",

volume = "16",

pages = "273--280",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "3",

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Kierdorf, K, Erny, D, Goldmann, T, Sander, V, Schulz, C , Perdiguero, EG, Wieghofer, P, Heinrich, A, Riemke, P, Hoelscher, C, Mueller, DN, Luckow, B, Brocker, T, Debowski, K, Fritz, G, Opdenakker, G, Diefenbach, A, Biber, K, Heikenwalder, M, Geissmann, F, Rosenbauer, F & Prinz, M 2013, 'Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways', Nature Neuroscience, vol. 16, no. 3, pp. 273-280. https://doi.org/10.1038/nn.3318

TY - JOUR

T1 - Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways

AU - Kierdorf, Katrin

AU - Erny, Daniel

AU - Goldmann, Tobias

AU - Sander, Victor

AU - Schulz, Christian

AU - Perdiguero, Elisa Gomez

AU - Wieghofer, Peter

AU - Heinrich, Annette

AU - Riemke, Pia

AU - Hoelscher, Christoph

AU - Mueller, Dominik N.

AU - Luckow, Bruno

AU - Brocker, Thomas

AU - Debowski, Katharina

AU - Fritz, Guenter

AU - Opdenakker, Ghislain

AU - Diefenbach, Andreas

AU - Biber, Knut

AU - Heikenwalder, Mathias

AU - Geissmann, Frederic

AU - Rosenbauer, Frank

AU - Prinz, Marco

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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.

KW - YOLK-SAC

KW - TRANSCRIPTION FACTORS

KW - FRACTALKINE RECEPTOR

KW - DENDRITIC CELLS

KW - MYELOID CELLS

KW - MACROPHAGES

KW - BRAIN

KW - DIFFERENTIATION

KW - HETEROGENEITY

KW - PROGENITORS

U2 - 10.1038/nn.3318

DO - 10.1038/nn.3318

M3 - Article

SN - 1097-6256

VL - 16

SP - 273

EP - 280

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 3

ER -

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

Abstract

Keywords

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