Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

Publication date: Available online 28 September 2017
Source:Cell
Author(s): Ki-Jun Yoon, Francisca Rojas Ringeling, Caroline Vissers, Fadi Jacob, Michael Pokrass, Dennisse Jimenez-Cyrus, Yijing Su, Nam-Shik Kim, Yunhua Zhu, Lily Zheng, Sunghan Kim, Xinyuan Wang, Louis C. Doré, Peng Jin, Sergi Regot, Xiaoxi Zhuang, Stefan Canzar, Chuan He, Guo-li Ming, Hongjun Song
N⁶-methyladenosine (m⁶A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m⁶A regulates mammalian brain development is unknown. Here, we show that m⁶A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m⁶A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m⁶A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m⁶A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m⁶A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m⁶A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m⁶A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

Graphical abstract

Teaser

m⁶A-dependent mRNA decay is critical for proper transcriptional prepatterning in mammalian cortical neurogenesis.


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