FMRP Modulates Neural Differentiation through m 6 A-Dependent mRNA Nuclear Export

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Animals, Newborn
  • Cell Cycle
  • Cell Differentiation*
  • Cell Proliferation
  • Cerebral Cortex / cytology
  • Fragile X Mental Retardation Protein / metabolism*
  • Gene Deletion
  • Karyopherins / metabolism
  • Mice, Knockout
  • Neural Stem Cells / metabolism
  • Neurons / cytology*
  • Neurons / metabolism*
  • RNA Transport*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism

Substances

  • Karyopherins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • exportin 1 protein
  • Fragile X Mental Retardation Protein
  • N6-methyladenosine (m6A)
  • Adenosine