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.
journal_name
Cell Resjournal_title
Cell researchauthors
Wu R,Li A,Sun B,Sun JG,Zhang J,Zhang T,Chen Y,Xiao Y,Gao Y,Zhang Q,Ma J,Yang X,Liao Y,Lai WY,Qi X,Wang S,Shu Y,Wang HL,Wang F,Yang YG,Yuan Zdoi
10.1038/s41422-018-0113-8subject
Has Abstractpub_date
2019-01-01 00:00:00pages
23-41issue
1eissn
1001-0602issn
1748-7838pii
10.1038/s41422-018-0113-8journal_volume
29pub_type
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