Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Early immune perturbations increase the risk of brain disorders, yet the mechanisms underlying the functional maturation of microglia, the brain resident immune cells, remain poorly defined. Here, we used mathematical modeling of hippocampus and cerebellum to reconstruct postnatal microglial development. We identified a proliferative-to-quiescent (P/Q) switch around P3/P4 that preceded the acquisition of morphological complexity and efficient phagocytosis and was accompanied by changes in cell-cycle dynamics and metabolic state. This P/Q switch was recapitulated in repopulation contexts in mice and in the fetal human brain. Pharmacological and genetic perturbations of proliferation impaired subsequent morphological complexity and phagocytosis efficiency. Finally, microglial developmental maturation was associated with chromatin remodeling and driven by the epigenetic regulator Ikaros. These findings uncover the milestones of microglial development, revealing a potential period of early vulnerability and establishing an unexpected linkage between proliferation and phagocytosis essential to understanding how these processes are coordinated in neurodegenerative disorders.