Dicer deficient adult microglia negatively impacts the process of demyelination and remyelination

Microglia, the resident immune cells of the central nervous system (CNS), are important regulators of normal brain activities. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Based on the observation of diminished Dicer positive microglia/macrophages number in demyelinating white matter lesions (WMLs) of human MS brains, here we probed the impact of impaired microRNA (miRNA)-mediated post-transcriptional gene regulation in a mouse model lacking microglia/macrophage-specific Dicer1 expression during demyelination and remyelination. Conditional Dicer1 ablation and loss of miRNAs expression in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting oligodendrocyte progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer1-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, finding from this study highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination. Overall design: To evaluate the effects of miRNA loss on microglial gene expression in tamoxifen -induced Dicer1 KO animals, adult Cx3cr1creERT2 mouse brain microglia (CD45int/Cd11b+) were flow-sorted and processed for RNA sequencing (RNA-seq). Three biological replicates of WT and KO mice microglia were analyzed for 4 conditions. 1-Naïve_only tamoxifen injected (3 Cre- and 3 Cre+), 2-Demyelination _tamoxifen injection at 4-5 weeks (CUP- 6w) (3 Cre- and 3 Cre+), 3-Remyelination_ tamoxifen injection at 4-5 weeks (CUP-6w+6w normal diet) (3Cre- and 3 Cre+), 4-Remyelination_Tamoxifen injected at 5w of CUP feeding (CUP-6w+6w normal diet) (3Cre- and 3 Cre+)