@article{fed28cfe4dc8431bab360caf7f60f10e,
title = "FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export",
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, mA, neural differentiation, neural stem cells, nuclear export, nuclear-cytoplasmic transport",
author = "Edens, {Brittany M.} and Caroline Vissers and Jing Su and Saravanan Arumugam and Zhaofa Xu and Han Shi and Nimrod Miller and {Rojas Ringeling}, Francisca and Ming, {Guo li} and Chuan He and Hongjun Song and Ma, {Yongchao C.}",
note = "Funding Information: This research was supported by grants from the NIH ( R01NS094564 and R21NS106307 to Y.C.M.; R37NS047344 , U19MH106434 , and P01NS097206 to H. Song; RM1HG008935 to C.H.; and R01MH105128 , R35NS097370 , and U19AI131130 to G.-l.M.); the Simons Foundation Autism Research Initiative (SAFRI) to H. Song ( 575050 ); Cure SMA and The Hartwell Foundation (to Y.C.M.); and the Chicago Biomedical Consortium (to Y.C.M. and C.H.). C.V. was partially supported by an NSF predoctoral fellowship and NIH T32GM007445 . We thank Dr. Stephanie Ceman for providing WT and ΔNES Fmr1 constructs, Dr. Anis Contractor for providing Fmr1 KO mice, and Dr. Xiaoxi Zhuang for sharing Mettl14 f/f mice. We thank Dr. Tian Shao for technical assistance in validating anti-FMRP antibodies. The research reported in this manuscript was made possible in part by the services of the Keck Biophysics Facility and the NUSeq Core Facility, which is supported by the Northwestern University Center for Genetic Medicine , the Feinberg School of Medicine , and the Shared and Core Facilities of Northwestern University{\textquoteright}s Office for Research . C.H. is a Howard Hughes Medical Institute Investigator. Y.C.M. is the Ann Marie and Francis Klocke M.D. Research Scholar supported by the Joseph and Bessie Feinberg Foundation . Funding Information: This research was supported by grants from the NIH (R01NS094564 and R21NS106307 to Y.C.M.; R37NS047344, U19MH106434, and P01NS097206 to H. Song; RM1HG008935 to C.H.; and R01MH105128, R35NS097370, and U19AI131130 to G.-l.M.); the Simons Foundation Autism Research Initiative (SAFRI) to H. Song (575050); Cure SMA and The Hartwell Foundation (to Y.C.M.); and the Chicago Biomedical Consortium (to Y.C.M. and C.H.). C.V. was partially supported by an NSF predoctoral fellowship and NIH T32GM007445. We thank Dr. Stephanie Ceman for providing WT and ?NES Fmr1 constructs, Dr. Anis Contractor for providing Fmr1 KO mice, and Dr. Xiaoxi Zhuang for sharing Mettl14f/f mice. We thank Dr. Tian Shao for technical assistance in validating anti-FMRP antibodies. The research reported in this manuscript was made possible in part by the services of the Keck Biophysics Facility and the NUSeq Core Facility, which is supported by the Northwestern University Center for Genetic Medicine, the Feinberg School of Medicine, and the Shared and Core Facilities of Northwestern University's Office for Research. C.H. is a Howard Hughes Medical Institute Investigator. Y.C.M. is the Ann Marie and Francis Klocke M.D. Research Scholar supported by the Joseph and Bessie Feinberg Foundation. B.M.E. and Y.C.M. designed the experiments and contributed to most of the aspects of the study. C.V. provided Mettl14cKO NPCs and contributed to fluorescence-activated cell sorting (FACS) cell-cycle analysis. J.S. and Z.X. contributed to qRT-PCR analysis. S.A. contributed to EMSA binding assays and mouse husbandry. H. Shi contributed to the RNA sequencing analysis. N.M. prepared many mouse RNA samples. F.R.R. and G.-l.M. provided the Dll1 m6A coverage plot. Y.C.M. C.H. and H. Song initiated the project. B.M.E. and Y.C.M. wrote the manuscript. Y.C.M. managed the project. C.H. is a scientific founder and scientific advisory board member of Accent Therapeutics, Inc. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = jul,
day = "23",
doi = "10.1016/j.celrep.2019.06.072",
language = "English (US)",
volume = "28",
pages = "845--854.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}