m6A mRNA Methylation Is Essential for Oligodendrocyte Maturation and CNS Myelination

Abstract

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N⁶-methyladenosine (m⁶A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m⁶A modification on numerous transcripts. In vivo conditional inactivation of an essential m⁶A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination.

Keywords: Mettl14; NF155; RNA epigenetic regulation; alternative splicing; m(6)A; mRNA methylation; myelin; oligodendrocyte development; oligodendrocyte precursor cells; oligodendrocytes.