Microglia cannibalism and efferocytosis leads to shorter lifespans of developmental microglia

by Hannah Gordon, Zachary T. Schafer, Cody J. Smith

The overproduction of cells and subsequent production of debris is a universal principle of neurodevelopment. Here, we show an additional feature of the developing nervous system that causes neural debris—promoted by the sacrificial nature of embryonic microglia that irreversibly become phagocytic after clearing other neural debris. Described as long-lived, microglia colonize the embryonic brain and persist into adulthood. Using transgenic zebrafish to investigate the microglia debris during brain construction, we identified that unlike other neural cell types that die in developmental stages after they have expanded, necroptosis-dependent microglial debris is prevalent when microglia are expanding in the zebrafish brain. Time-lapse imaging of microglia demonstrates that this debris is cannibalized by other microglia. To investigate features that promote microglia death and cannibalism, we used time-lapse imaging and fate-mapping strategies to track the lifespan of individual developmental microglia. These approaches revealed that instead of embryonic microglia being long-lived cells that completely digest their phagocytic debris, once most developmental microglia in zebrafish become phagocytic they eventually die, including ones that are cannibalistic. These results establish a paradox—which we tested by increasing neural debris and manipulating phagocytosis—that once most microglia in the embryo become phagocytic, they die, create debris, and then are cannibalized by other microglia, resulting in more phagocytic microglia that are destined to die.