The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental...

Myeloid progenitor cells colonize the brain during embryogenesis and differentiate in microglia. Microglia shape neuronal wiring during development and maintain brain homeostasis in adulthood, both actions requiring intact cytoskeletal functionality. The Wiskott-Aldrich syndrome protein (WASp) mediates cytoskeletal dynamics of peripheral myeloid cells, suggesting a similar role in microglia. To investigate WASp's role in microglia, we impaired WASp function in human induced pluripotent stem cells-derived microglia (iMicro) and zebrafish embryos.WASp colocalized with the actin cytoskeleton at membrane ruffles in phagocytic iMicro and appeared required for their phagocytic function. When co-cultured with neuronal cells, the support of iMicro with defective WASp function to neuronal wiring was impaired. Similarly, zebrafish embryos exposed to WASp inhibition showed brain accumulation of uncleared apoptotic bodies, reduced brain colonization of myeloid cells, and impaired sensorimotor response to mechanical stimuli.These findings identify WASp as a regulator of microglial phagocytosis and cytoskeletal dynamics, with implication in neuronal wiring during neurodevelopment.