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Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways
Katrin Kierdorf1, Daniel Erny, Tobias Goldmann
1Department of Neuropathology, University of Freiburg, Freiburg, Germany.
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.
Insights
Mouse microglia originate from primitive erythromyeloid precursors in the yolk sac. Key transcription factors like Pu.1 and Irf8 are crucial for microgliogenesis and brain immune cell development.
Area of Science:
- Neuroimmunology
- Developmental Biology
- Hematopoiesis
Background:
- Microglia are the primary immune cells in the central nervous system, originating from extraembryonic tissues.
- The precise cellular origins and molecular mechanisms governing microglial development remain incompletely understood.
Purpose of the Study:
- To identify the specific precursors of microglia and elucidate the transcriptional program regulating their development.
- To understand the cellular and molecular pathways involved in microglial colonization of the developing brain.
Main Methods:
- Analysis of yolk sac erythromyeloid precursors at embryonic day 8.
- Characterization of cell surface markers (CD45, c-kit, CX3CR1, CD31, F4/80, MCSF-R) to define developmental stages.
- Investigation of the role of transcription factors (Pu.1/Sfpi, Irf8, Myb, Id2, Batf3, Klf4) in microgliogenesis using knockout models.
- Assessment of matrix metalloproteinases involved in brain invasion.
Main Results:
- Mouse microglia are derived from primitive c-kit(+) erythromyeloid precursors in the yolk sac.
- Precursors differentiate into immature (A1) and mature (A2) populations, marked by specific cell surface proteins.
- Microgliogenesis requires Pu.1 and Irf8, with Irf8 being essential for A2 cell development.
- Myb, Id2, Batf3, and Klf4 were not found to be essential for this process.
- Mature microglia (A2 cells) invade the developing brain via matrix metalloproteinases.
Conclusions:
- The study identifies primitive erythromyeloid precursors as the source of microglia.
- Irf8 is identified as a critical transcription factor for the development of mature microglial precursors.
- This work provides significant cellular and molecular insights into the origin and developmental trajectory of brain-resident immune cells.
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