Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway

Cell Rep. 2014 Feb 27;6(4):748-64. doi: 10.1016/j.celrep.2014.01.028. Epub 2014 Feb 13.


The mechanisms dictating whether a cell proliferates or differentiates have undergone intense scrutiny, but they remain poorly understood. Here, we report that UPF1, a central component in the nonsense-mediated RNA decay (NMD) pathway, plays a key role in this decision by promoting the proliferative, undifferentiated cell state. UPF1 acts, in part, by destabilizing the NMD substrate encoding the TGF-β inhibitor SMAD7 and stimulating TGF-β signaling. UPF1 also promotes the decay of mRNAs encoding many other proteins that oppose the proliferative, undifferentiated cell state. Neural differentiation is triggered when NMD is downregulated by neurally expressed microRNAs (miRNAs). This UPF1-miRNA circuitry is highly conserved and harbors negative feedback loops that act as a molecular switch. Our results suggest that the NMD pathway collaborates with the TGF-β signaling pathway to lock in the stem-like state, a cellular state that is stably reversed when neural differentiation signals that induce NMD-repressive miRNAs are received.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cells, Cultured
  • Feedback, Physiological
  • Gene Expression Regulation, Developmental*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Molecular Sequence Data
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurogenesis*
  • Nonsense Mediated mRNA Decay*
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / metabolism
  • Xenopus


  • MicroRNAs
  • Rent1 protein, mouse
  • Smad7 Protein
  • Smad7 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta