CNS macrophage populations differentially rely on an intronic Csf1r enhancer for their development

The central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia and BAMs emerge following the early lineage divergence of a common embryonic progenitor in the yolk sac. 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 this mutation also impacts BAM arrival and/or maintenance. Here, we show that intracerebroventricular macrophages, including Kolmer’s epiplexus macrophages, are absent in embryonic and adult Csf1rΔFIRE/ΔFIRE mice. Stromal choroid plexus BAMs are also considerably reduced. We demonstrate that macrophages arrive in brain ventricles from embryonic day 10.5, and can traverse ventricular walls to enter ventricles in embryonic slice cultures. In Csf1rΔFIRE/ΔFIRE embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, while the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results indicate that microglia and BAMs differentially rely on FIRE shortly after their developmental programmes diverge, and support the concept that intracerebroventricular macrophages are microglia-like cells.