In inflammatory CNS conditions such as multiple sclerosis (MS),

SignificanceProper communication between brain regions, via white matter tracts, allows us to carry out complex cognitive and motor tasks. Impulses traveling must arrive at relay points almost simultaneously for such communication to be effective. Myelin enables saltatory conduction of impulses and hence is a candidate for modulation of impulse conduction velocity. But myelin structure, once formed, has been considered static. In this study, we show that mature myelin structure is dynamic. The mature myelin sheath thickness and nodal gap length can be reversibly modulated to optimize the speed of axonal impulses. This modulation of myelin is regulated by exocytosis of thrombin protease inhibitors from astrocytes at the node of Ranvier.

Summary Oligodendrocytes derive from progenitors (OPC) through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPC and yet, genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis, but was characterized by a profound defect of differentiation, associated with changes in exon-skipping and intron-retention splicing events and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPC is not sufficient to induce a lineage switch, but acts as an important determinant of the coordination between RNA splicing and protein synthesis, necessary for myelin formation.