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A novel m6A reader Prrc2a controls oligodendroglial specification and myelination.

ABSTRACT: 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.

SUBMITTER: Wu R

PROVIDER: S-EPMC6318280 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A novel m6A reader Prrc2a controls oligodendroglial specification and myelination.

Wu Rong R Li Ang A Sun Baofa B Sun Jian-Guang JG Zhang Jinhua J Zhang Ting T Chen Yusheng Y Xiao Yujie Y Gao Yuhao Y Zhang Qingyang Q Ma Jun J Yang Xin X Liao Yajin Y Lai Wei-Yi WY Qi Xiaolong X Wang Shukun S Shu Yousheng Y Wang Hai-Lin HL Wang Fengchao F Yang Yun-Gui YG Yuan Zengqiang Z

Cell research 20181204 1

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 hypomyelinat ...[more]

PMID: 30514900

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A novel m6A reader Prrc2a controls oligodendroglial specification and myelination.

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A novel m<sup>6</sup>A reader Prrc2a controls oligodendroglial specification and myelination.

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