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Cell Rep. 2019 Jul 23;28(4):845-854.e5. doi: 10.1016/j.celrep.2019.06.072.

FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export.

Author information

1
Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
2
Biochemistry, Molecular and Cellular Biology Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Gene Center, Ludwig-Maximilians-Universität München, Munich 81377, Germany.
4
Department of Neuroscience and Mahoney Institute for Neuroscience, Department of Cell and Developmental Biology, Institute for Regeneration, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Departments of Chemistry and Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
6
Department of Neuroscience and Mahoney Institute for Neuroscience, Department of Cell and Developmental Biology, Institute for Regeneration, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.
7
Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA. Electronic address: ma@northwestern.edu.

Abstract

N6-methyladenosine (m6A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads m6A to promote nuclear export of methylated mRNA targets during neural differentiation. Fmr1 knockout (KO) mice show delayed neural progenitor cell cycle progression and extended maintenance of proliferating neural progenitors into postnatal stages, phenocopying methyltransferase Mettl14 conditional KO (cKO) mice that have no m6A modification. RNA-seq and m6A-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of m6A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m6A and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds m6A-modified RNAs to facilitate their nuclear export through CRM1. The nuclear retention defect can be mitigated by wild-type but not nuclear export-deficient FMRP, establishing a critical role for FMRP in mediating m6A-dependent mRNA nuclear export during neural differentiation.

KEYWORDS:

FMRP; Fmr1 knockout; Mettl14; RNA methylation; fragile X syndrome; m(6)A; neural differentiation; neural stem cells; nuclear export; nuclear-cytoplasmic transport

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