Two distinct ontogenies confer heterogeneity to mouse brain microglia.

mutant mice show compulsive behavior similar to trichotillomania, a human obsessive-compulsive-spectrum disorder. The only lineage-labeled cells in the brains of mice are microglia, suggesting that defective microglia caused the disorder. What is the source of the microglia? It has been posited that all microglia progenitors arise at embryonic day (E) 7.5 during yolk sac hematopoiesis, and colonize the brain at E9.5. In contrast, we show the presence of two microglia subpopulations: canonical, non- microglia and microglia. Unlike non- microglia, microglia progenitors appear to be generated during the second wave of yolk sac hematopoiesis, then detected in the aorto-gonad-mesonephros (AGM) and fetal liver, where they are greatly expanded, prior to infiltrating the E12.5 brain. Further, we demonstrate that hematopoietic progenitor cells taken from fetal liver are competent to give rise to microglia Although the two microglial subpopulations are very similar molecularly, and in their response to brain injury and participation in synaptic pruning, they show distinct brain distributions which might contribute to pathological specificity. Non- microglia significantly outnumber microglia, but they cannot compensate for the loss of function in microglia, suggesting further crucial differences between the two subpopulations.