Microglial cathepsin B is necessary for neuronal efferocytosis in zebrafish and mice during brain development

Abstract Half of all newborn neurons in the developing brain are removed via efferocytosis - the phagocytic clearance of apoptotic cells. Microglia are brain-resident professional phagocytes that play important roles in neural circuit development including as primary effectors of efferocytosis. While the mechanisms through which microglia recognize potential phagocytic cargo are widely studied, the lysosomal mechanisms that are necessary for efficient digestion are less well defined. Here we show that the lysosomal protease cathepsin B is enriched in microglia located in brain regions where neuronal turnover is high in both zebrafish and mouse. Genetic disruption of cathepsin B in zebrafish and mice had an accumulation of microglia containing undigested dead cells. Live imaging studies in zebrafish and in cultured mouse microglia revealed fewer phagocytic events and reduced overall phagocytosis. We also observed behavioral impairments in both models. These data reveal a role for microglial cathepsin B in vertebrate brain development.