title: Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation and Motility.
abstract: Loss-of-function mutations in the cytosine-5 RNA methylase NSUN2 cause neurodevelopmental disorders in humans, yet the underlying cellular processes leading to the symptoms that include microcephaly remain unclear. Here, we show that NSUN2 is expressed in early neuroepithelial progenitors of the developing human brain, and its expression is gradually reduced during differentiation of human neuroepithelial stem (NES) cells in vitro. In the developing Nsun2-/-mouse cerebral cortex, intermediate progenitors accumulate and upper-layer neurons decrease. Loss of NSUN2-mediated methylation of tRNA increases their endonucleolytic cleavage by angiogenin, and 5' tRNA fragments accumulate in Nsun2-/-brains. Neural differentiation of NES cells is impaired by both NSUN2 depletion and the presence of angiogenin. Since repression of NSUN2 also inhibited neural cell migration toward the chemoattractant fibroblast growth factor 2, we conclude that the impaired differentiation capacity in the absence of NSUN2 may be driven by the inability to efficiently respond to growth factors.
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Joana V
authors.initials: JV
authors.lastname: Flores
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors.forename: Lucía
authors.initials: L
authors.lastname: Cordero-Espinoza
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Feride
authors.initials: F
authors.lastname: Oeztuerk-Winder
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Andersson-Rolf
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Selmi
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Blanco
authors.affiliation: Department of Neurosurgery, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
authors.forename: Jignesh
authors.initials: J
authors.lastname: Tailor
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Sabine
authors.initials: S
authors.lastname: Dietmann
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK. Electronic address: mf364@cam.ac.uk.
authors.forename: Michaela
authors.initials: M
authors.lastname: Frye
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement; D003596:Cytosine / Q000378:metabolism*; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D012313:RNA / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000494:pharmacology
chemical_list: D012313:RNA; D003596:Cytosine; D008780:Methyltransferases; C513146:Misu protein, mouse; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: 5-methylcytosine; NSUN2; RNA methylation; neural stem cells; neurodevelopmental disorder