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

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          SUMMARY

          N 6-methyladenosine (m 6A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads m 6A 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 m 6A modification. RNA-seq and m 6A-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of m 6A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m 6A and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds m 6A-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 m 6A-dependent mRNA nuclear export during neural differentiation.

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          In Brief

          Edens et al. reveal fragile X mental retardation protein (FMRP) as an m 6A reader that promotes the nuclear export of methylated mRNAs during neural differentiation. Loss of either Fmr1 or the m 6A methyltransferase Mettl14 results in the nuclear accumulation of neural differentiation-related mRNAs, causing delayed neural progenitor differentiation in mice.

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          Most cited references24

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          Specification of cerebral cortical areas.

          P Rakic (1988)
          How the immense population of neurons that constitute the human cerebral neocortex is generated from progenitors lining the cerebral ventricle and then distributed to appropriate layers of distinctive cytoarchitectonic areas can be explained by the radial unit hypothesis. According to this hypothesis, the ependymal layer of the embryonic cerebral ventricle consists of proliferative units that provide a proto-map of prospective cytoarchitectonic areas. The output of the proliferative units is translated via glial guides to the expanding cortex in the form of ontogenetic columns, whose final number for each area can be modified through interaction with afferent input. Data obtained through various advanced neurobiological techniques, including electron microscopy, immunocytochemistry, [3H]thymidine and receptor autoradiography, retrovirus gene transfer, neural transplants, and surgical or genetic manipulation of cortical development, furnish new details about the kinetics of cell proliferation, their lineage relationships, and phenotypic expression that favor this hypothesis. The radial unit model provides a framework for understanding cerebral evolution, epigenetic regulation of the parcellation of cytoarchitectonic areas, and insight into the pathogenesis of certain cortical disorders in humans.
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            N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

            A comprehensive proteomics screen for ‘reader’ proteins that recognize m6A-modified RNA reveals that the modification both promotes and prevents the binding of factors that control mRNA homeostasis in mammalian cells.
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              Dysregulation and restoration of translational homeostasis in fragile X syndrome.

              Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                30 July 2019
                23 July 2019
                08 August 2019
                : 28
                : 4
                : 845-854.e5
                Affiliations
                [1 ]Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
                [2 ]Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
                [3 ]Biochemistry, Molecular and Cellular Biology Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
                [4 ]Gene Center, Ludwig-Maximilians-Universität München, Munich 81377, Germany
                [5 ]Department of Neuroscience and Mahoney Institute for Neuroscience, Department of Cell and Developmental Biology, Institute for Regeneration, University of Pennsylvania, Philadelphia, PA 19104, USA
                [6 ]Departments of Chemistry and Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
                [7 ]Lead Contact
                Author notes

                AUTHOR CONTRIBUTIONS

                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 m 6A 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.

                Article
                NIHMS1535564
                10.1016/j.celrep.2019.06.072
                6687293
                31340148
                85d18835-2a91-45fc-a6e0-6fce7c242632

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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