biostudies-literatureUnknown29(1)Wu RWhile N⁶-methyladenosine (m⁶A), the most abundant internal modification in eukaryotic mRNA, is linked to cell differentiation and tissue development, the biological significance of m⁶A modification in mammalian glial development remains unknown. Here, we identify a novel m⁶A reader, Prrc2a (Proline rich coiled-coil 2 A), which controls oligodendrocyte specification and myelination. Nestin-Cre-mediated knockout of Prrc2a induces significant hypomyelination, decreased lifespan, as well as locomotive and cognitive defects in a mouse model. Further analyses reveal that Prrc2a is involved in oligodendrocyte progenitor cells (OPCs) proliferation and oligodendrocyte fate determination. Accordingly, oligodendroglial-lineage specific deletion of Prrc2a causes a similar phenotype of Nestin-Cre-mediated deletion. Combining transcriptome-wide RNA-seq, m⁶A-RIP-seq and Prrc2a RIP-seq analysis, we find that Olig2 is a critical downstream target gene of Prrc2a in oligodendrocyte development. Furthermore, Prrc2a stabilizes Olig2 mRNA through binding to a consensus GGACU motif in the Olig2 CDS (coding sequence) in an m⁶A-dependent manner. Interestingly, we also find that the m⁶A demethylase, Fto, erases the m⁶A modification of Olig2 mRNA and promotes its degradation. Together, our results indicate that Prrc2a plays an important role in oligodendrocyte specification through functioning as a novel m⁶A reader. These findings suggest a new avenue for the development of therapeutic strategies for hypomyelination-related neurological diseases.Cell research23-41https://www.ebi.ac.uk/biostudies/studies/S-EPMC6318280biostudies-literatureA novel m⁶A reader Prrc2a controls oligodendroglial specification and myelination.PMC6318280Wang HLLiao YYang YGZhang JSun BXiao YWang FZhang QYang XZhang TSun JGQi XWang SGao YWu RLai WYLi AChen YMa JShu YYuan ZfalseA novel m⁶A reader Prrc2a controls oligodendroglial specification and myelination.While N⁶-methyladenosine (m⁶A), the most abundant internal modification in eukaryotic mRNA, is linked to cell differentiation and tissue development, the biological significance of m⁶A modification in mammalian glial development remains unknown. Here, we identify a novel m⁶A reader, Prrc2a (Proline rich coiled-coil 2 A), which controls oligodendrocyte specification and myelination. Nestin-Cre-mediated knockout of Prrc2a induces significant hypomyelination, decreased lifespan, as well as locomotive and cognitive defects in a mouse model. Further analyses reveal that Prrc2a is involved in oligodendrocyte progenitor cells (OPCs) proliferation and oligodendrocyte fate determination. Accordingly, oligodendroglial-lineage specific deletion of Prrc2a causes a similar phenotype of Nestin-Cre-mediated deletion. Combining transcriptome-wide RNA-seq, m⁶A-RIP-seq and Prrc2a RIP-seq analysis, we find that Olig2 is a critical downstream target gene of Prrc2a in oligodendrocyte development. Furthermore, Prrc2a stabilizes Olig2 mRNA through binding to a consensus GGACU motif in the Olig2 CDS (coding sequence) in an m⁶A-dependent manner. Interestingly, we also find that the m⁶A demethylase, Fto, erases the m⁶A modification of Olig2 mRNA and promotes its degradation. Together, our results indicate that Prrc2a plays an important role in oligodendrocyte specification through functioning as a novel m⁶A reader. These findings suggest a new avenue for the development of therapeutic strategies for hypomyelination-related neurological diseases.2019-01-01T00:00:00Z2019 Jan2024-11-12T18:17:36.538Z2019-03-26T22:39:25ZS-EPMC63182803051490010.1038/s41422-018-0113-8