Abstract
SummaryLoss-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.
Highlights
Human brain development begins with the differentiation of neural progenitor cells in the third gestational week and extends through to adolescence (Stiles and Jernigan, 2010)
RNA modifications are crucial for development and aberrant deposition of RNA modifications can lead to complex human diseases, including neurodevelopmental disorders and cancer (Frye and Blanco, 2016; Popis et al, 2016)
Nucleolar expression of NSUN2 overlapped with SOX1, a marker for early neuroepithelial progenitors in the neural tube (Figures 1A and 1B)
Summary
Human brain development begins with the differentiation of neural progenitor cells in the third gestational week and extends through to adolescence (Stiles and Jernigan, 2010). The first cells committed to a neural fate appear during gastrulation in a single sheet of cells with epithelial features (Stern, 2005). These neuroepithelial stem (NES) cells differentiate further into multiple types of cells, including neurons, astrocytes, and other glial cells (Temple, 2001). The brain is the most complex organ and its formation requires a tight control of lineage-specific differentiation pathways. Gene expression is dynamically controlled through reversible chemical modifications in DNA and histones (Bannister and Kouzarides, 2011; Deaton and Bird, 2011). RNA modifications are crucial for development and aberrant deposition of RNA modifications can lead to complex human diseases, including neurodevelopmental disorders and cancer (Frye and Blanco, 2016; Popis et al, 2016)
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