QUAKING Regulates Microexon Alternative Splicing of the Rho GTPase Pathway and Controls Microglia Homeostasis

The role of RNA binding proteins in regulating the phagocytic and cytokine-releasing functions of microglia is unknown. Here, we show that microglia deficient for the QUAKING (QKI) RNA binding protein have increased proinflammatory cytokine release and defects in processing phagocytosed cargo. Splicing analysis reveals a role for QKI in regulating microexon networks of the Rho GTPase pathway. We show an increase in RhoA activation and proinflammatory cytokines in QKI-deficient microglia that are repressed by treating with a Rock kinase inhibitor. During the cuprizone diet, mice with QKI-deficient microglia are inefficient at supporting central nervous system (CNS) remyelination and cause the recruited oligodendrocyte precursor cells to undergo apoptosis. Furthermore, the expression of QKI in microglia is downregulated in preactive, chronic active, and remyelinating white matter lesions of multiple sclerosis (MS) patients. Overall, our findings identify QKI as an alternative splicing regulator governing a network of Rho GTPase microexons with implications for CNS remyelination and MS patients. [Display omitted] •QKI regulates microexon splicing of genes involved in the Rho GTPase pathway•QKI depletion induces an inflammatory phenotype with defects in phagocytosis•The remyelination process is hindered in mice containing QKI-deficient microglia•The QKI-5 expression is significantly reduced near lesions in MS patients Lee et al. report that the deletion of QKI in microglia causes a proinflammatory phenotype with defects in the processing of phagocytosed cargo. Genome-wide analysis shows that QKI regulates splicing of a microexon network of the Rho GTPase pathway in microglia. Thus, RhoA GTPase and Rock2 are activated in QKI-deficient microglia.