A novel m6A reader Prrc2a controls oligodendroglial specification and myelination
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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 Prrc2o causes a similar phenotype of Nestin-Cre-mediated deletion.Combining transcfiptome-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.
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We sincerely thank Dr. Wei Mo for providing cells lines and the guide of OPCs culture.We thank Dr. Bo Xiao and Dr. Pumin Zhang for providing the mouse lines. We thank the members of the Yuan laboratory and Dr. Yizheng Wang for helpful discussions and technical help. We thank BIG sequencing core faciGrant 81630026, 81125010, 81030025 to ZY, 31625016. 31430022 to Y-G Y,31670824 to B-F S, 31600946 to SW;the Beijing Nature Science Foundation7132147 to ZY;the National Basic Research Program of China2016YFC0900300;CAS Strategic Priority Research Program XDB14030300, QYZDY-SSW-SMC027 to Y-G Y.Shanghai Municipal Science and Technology Major Project Grant No.2017SHZDZX01 to Y-G Y. China Postdoctoral Science Foundation Grant No.2017M613408 to RW
