TY - JOUR
T1 - Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation and Motility
AU - Flores, Joana V.
AU - Cordero-Espinoza, Lucía
AU - Oeztuerk-Winder, Feride
AU - Andersson-Rolf, Amanda
AU - Selmi, Tommaso
AU - Blanco, Sandra
AU - Tailor, Jignesh
AU - Dietmann, Sabine
AU - Frye, Michaela
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/1/10
Y1 - 2017/1/10
N2 - 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.
AB - 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.
KW - 5-methylcytosine
KW - NSUN2
KW - RNA methylation
KW - neural stem cells
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85009100579&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2016.11.014
DO - 10.1016/j.stemcr.2016.11.014
M3 - Article
C2 - 28041877
AN - SCOPUS:85009100579
SN - 2213-6711
VL - 8
SP - 112
EP - 124
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 1
ER -