Developmental Apoptosis Mediates Entry and Positioning of Microglia in the Zebrafish Brain

In the brain, neurons that fail to assemble into functional circuits are eliminated. Their clearance depends on microglia, immune cells that colonize the CNS during embryogenesis. Despite the importance of these cells in development and disease, the mechanisms that target and position microglia within the brain are unclear. Here we show that, in zebrafish, attraction of microglia into the brain exploits differences in developmental neuronal apoptosis and that these provide a mechanism for microglial distribution. Reducing neuronal cell death results in fewer microglia, whereas increased apoptosis enhances brain colonization, resulting in more microglia at later stages. Interestingly, attraction into the brain depends on nucleotide signaling, the same signaling system used to guide microglia toward brain injuries. Finally, this work uncovers a cell-non-autonomous role for developmental apoptosis. Classically considered a wasteful process, programmed cell death is exploited here to configure the immune-neuronal interface of the brain. [Display omitted] •Neuronal apoptosis attracts committed microglial precursors into the brain•Apoptosis-driven attraction depends on nucleotide signaling•Developmental apoptosis configures the immune-neuronal interface of the brain Casano et al. show that establishment of the microglial population is linked to developmental apoptosis in the brain. Differences in neuronal apoptosis provide a mechanism for entry and positioning of microglial precursors within the brain. Attraction is mediated by nucleotide signaling previously shown to guide microglia toward brain injuries.