FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export

Brittany M. Edens, Caroline Vissers, Jing Su, Saravanan Arumugam, Zhaofa Xu, Han Shi, Nimrod Miller, Francisca Rojas Ringeling, Guo li Ming, Chuan He, Hongjun Song*, Yongchao C. Ma

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)845-854.e5
JournalCell reports
Volume28
Issue number4
DOIs
StatePublished - Jul 23 2019

Keywords

  • FMRP
  • Fmr1 knockout
  • Mettl14
  • RNA methylation
  • fragile X syndrome
  • mA
  • neural differentiation
  • neural stem cells
  • nuclear export
  • nuclear-cytoplasmic transport

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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