The Arp2/3 complex controls the development of homeostatic microglia.

Microglial dynamics and homeostasis are crucial for maintaining central nervous system (CNS) function. To fulfill their homeostatic functions, microglia develop into ramified cells with highly dynamic cell protrusions. However, the detailed mechanisms underlying this developmental transition are largely unknown. Here, we investigate the role of the Actin-related protein 2/3 (Arp2/3) complex, a critical actin nucleator that controls the formation of actin branches, for the biology of tissue-resident microglia. By conditionally targeting Arpc4 in mice, we show that Arp2/3 depletion in tissue-resident microglia causes phenotypes beyond previously reported functions in other immune cell types. Our results identify an important role of Arp2/3 for controlling the developmental transition of microglia into cells with ramified morphology, homeostatic gene profile, and surveillance function in the CNS. Together, our results link actin remodeling to microglial maturation and activation, highlighting the Arp2/3 complex as a critical factor for maintaining the plasticity and preventing pathological activation of endogenous microglia.