1Arp2/3 complex controls microglial cell dynamics and homeostasis by regulating TGF-ß signaling.

Microglia are the major brain-resident immune cell subsetthat areessential during pathology and physiology in the central nervous system. The regulation of functional elementsrequired for microglialhomeostasis needsto be precisely orchestrated.To date, the underlying mechanismshave not been fully investigated. Here,we show that actin network dynamics mediated by the Arp2/3 complex play a crucial role in microglial cell function. Upon interruption of Arp2/3 complex integrity in the conditional knockoutmouse model, we found significant alterations in microglial cell morphology, motility, and chemotaxisfunction.Transcriptomics analysis revealedthat Arp2/3-deficient microglia downregulatehomeostatic signature and upregulatecell activationthat isassociated with APOE induction, Ms4a7upregulation,and TGF?signaling impairment. In vitrostudies confirm that the Arp2/3 downstream actin-related molecules are required for mediating the TGF?signaling pathway in microglia. Our resultsshow that the Arp2/3complexis required for microglia cell dynamics and plays a key role in maintaining microglial cell homeostasis by regulating the TGF-ß signaling. Overall design: scRNA-seq of CD45+ cells from control and Arpc4dCx3cr1 mice