Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation and Motility

Joana V. Flores, Lucía Cordero-Espinoza, Feride Oeztuerk-Winder, Amanda Andersson-Rolf, Tommaso Selmi, Sandra Blanco, Jignesh Tailor, Sabine Dietmann, Michaela Frye

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

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.

Original languageEnglish
Pages (from-to)112-124
Number of pages13
JournalStem Cell Reports
Volume8
Issue number1
DOIs
StatePublished - Jan 10 2017

Keywords

  • 5-methylcytosine
  • NSUN2
  • RNA methylation
  • neural stem cells
  • neurodevelopmental disorder

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