Dicer deficiency in microglia leads to accelerated demyelination and failed remyelination

Abstract

SummaryMicroglia are the resident immune cells of the central nervous system (CNS) and are important regulators of normal brain functions. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Here we probed the impact of microRNA (miRNA)-mediated post-transcriptional gene regulation using a mouse model lacking microglia/macrophage-specificDicerexpression during demyelination and remyelination. ConditionalDicerablation and loss of miRNAs in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting OL progenitor cells (OPCs) in the precursor stage. At the transcriptional level,Dicer-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, these results 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.Graphical Abstract