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Author Notes:

Guo-li Ming (gming@mail.med.upenn.edu) and Hongjun Song (shongjun@mail.med.upenn.edu).

AUTHOR CONTRIBUTIONS: K-J. Y. led the project and contributed to all aspects of the study.

F.R.R. performed m6A-seq, RNA-seq, and bioinformatics analysis.

C.V. contributed to most aspects of the study.

F.J. contributed to human NPC and organoid analysis.

M.P. and S.R. contributed to timelapse imaging analysis of cell cycle.

D.J-C., Y.S., N-S.K., Y.Z., L.Z., S.K., X.W. and P.J. contributed to additional data collection and analyses.

L.C.D., X.Z. and C.H. contributed Mett1 f/f mice. S.C. contributed to bioinformatics analyses.

G-l.M., H.S. and K-J.Y. conceived the project.

K-J. Y., F.R.R., C.V., G-l. M., and H.S. wrote the manuscript.

We thank K.M. Christian and J. Schnoll for comments, members of Ming and Song laboratories for discussion, L. Liu, Y. Cai, and D.G. Johnson for technical assistance, and T. M. Hyde and D. R. Weinberger for dissected fetal human brain samples.

Subjects:

Research Funding:

K-J.Y. was partially supported by a Young Investigator Award from Brain & Behavior Research Foundation and a postdoctoral fellowship from Maryland Stem Cell Research Found (MSCRF); C.V. was partially supported by an NSF pre-doctoral fellowship and NIH T32GM007445.

The research was supported by grants from NIH (R37NS047344 to H.S., U19MH106434 to H.S and G-l.M., P01NS097206 to H.S., G-l.M., P.J and C.H., R01MH105128 and R35NS097370 to G-l.M., U19AI131130 to G-l.M. and P.J., R01NS051630 and R01MH102690 to P.J, RM1HG008935 to C.H., H.S and P.J), Simons Foundation (to H.S. and G-l.M.), and The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G-l.M.).

C.H. is a Howard Hughes Medical Institute Investigator.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • RNA METHYLATION
  • SCHIZOPHRENIA
  • EXPRESSION
  • NEURONS
  • CELLS
  • IDENTIFICATION
  • MECHANISMS
  • NEWBORN
  • MODEL
  • SUITE

Temporal Control of Mammalian Cortical Neurogenesis by m(6)A Methylation

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Journal Title:

Analytical Cellular Pathology / Cellular Oncology

Volume:

Volume 171, Number 4

Publisher:

, Pages 877-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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

Copyright information:

© 2017 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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