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Published on: July 17, 2017
CNS macrophages differentially rely on an intronic Csf1r enhancer for their development
David A D Munro1, Barry M Bradford2, Samanta A Mariani3
1UK Dementia Research Institute at The University of Edinburgh, Chancellor's Building, Edinburgh EH16 4SB, UK.
Abstract:
The central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia, but not BAMs, were reported to be absent in mice lacking a conserved Csf1r enhancer: the fms-intronic regulatory element (FIRE). However, it is unknown whether FIRE deficiency also impacts BAM arrival and/or maintenance. Here, we show that macrophages in the ventricular system of the brain, including Kolmer's epiplexus macrophages, are absent in Csf1rΔFIRE/ΔFIRE mice. Stromal choroid plexus BAMs are also considerably reduced. During normal development, we demonstrate that intracerebroventricular macrophages arrive from embryonic day 10.5, and can traverse ventricular walls in embryonic slice cultures. In Csf1rΔFIRE/ΔFIRE embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, whereas the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results provide new insights into the development and regulation of different CNS macrophage populations.
Insights
The study reveals that the fms-intronic regulatory element (FIRE) is crucial for the development of brain macrophages, including microglia and border-associated macrophages (BAMs). Its absence eliminates microglia and severely impacts BAMs, highlighting FIRE's essential role in CNS macrophage regulation.
Area of Science:
- Neuroimmunology
- Developmental Biology
- Macrophage Biology
Background:
- The central nervous system (CNS) contains parenchymal microglia and non-parenchymal border-associated macrophages (BAMs).
- Previous studies indicated that microglia, but not BAMs, are absent in mice lacking the conserved Csf1r enhancer, the fms-intronic regulatory element (FIRE).
- The impact of FIRE deficiency on BAM arrival and maintenance remained unclear.
Purpose of the Study:
- To investigate the role of the fms-intronic regulatory element (FIRE) in the development and regulation of CNS macrophage populations.
- To determine whether FIRE deficiency affects the arrival and/or maintenance of border-associated macrophages (BAMs).
Main Methods:
- Analysis of macrophage populations in Csf1rΔFIRE/ΔFIRE mice.
- Assessment of intracerebroventricular macrophage development and migration.
- Utilizing embryonic slice cultures to study macrophage traversal of ventricular walls.
Main Results:
- Macrophages in the brain's ventricular system, including Kolmer's epiplexus macrophages, were absent in Csf1rΔFIRE/ΔFIRE mice.
- Stromal choroid plexus BAMs were significantly reduced in Csf1rΔFIRE/ΔFIRE mice.
- FIRE deficiency eliminated the arrival of primitive microglia and intracerebroventricular macrophages, while partially restricting cephalic mesenchyme and stromal choroid plexus BAM arrival.
Conclusions:
- The fms-intronic regulatory element (FIRE) is essential for the development of both microglia and specific BAM populations within the CNS.
- FIRE plays a critical role in regulating the arrival of macrophages into the developing brain.
- These findings offer novel insights into the distinct developmental pathways and regulatory mechanisms governing CNS macrophage populations.
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