NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure

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  • Taesun Eom
    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
  • Chaolin Zhang
    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
  • Huidong Wang
    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
  • Kenneth Lay
    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
  • John Fak
    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
  • Jeffrey L Noebels
    Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, United States
  • Robert B Darnell
    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States

Description

<jats:p>The neuronal RNA binding protein NOVA regulates splicing, shuttles to the cytoplasm, and co-localizes with target transcripts in dendrites, suggesting links between splicing and local translation. Here we identified >200 transcripts showing NOVA-dependent changes in abundance, but, surprisingly, HITS-CLIP revealed NOVA binds these RNAs in introns rather than 3′ UTRs. This led us to discover NOVA-regulated splicing of cryptic exons within these introns. These exons triggered nonsense mediated decay (NMD), as UPF1 and protein synthesis were required for NOVA's effect on RNA levels. Their regulation was dynamic and physiologically relevant. The NMD exons were regulated by seizures, which also induced changes in Nova subcellular localization and mediated large changes in synaptic proteins, including proteins implicated in familial epilepsy. Moreover, Nova haploinsufficient mice had spontaneous epilepsy. The data reveal a hidden means of dynamic RNA regulation linking electrical activity to splicing and protein output, and of mediating homeostatic excitation/inhibition balance in neurons.</jats:p>

Journal

  • eLife

    eLife 2 2013-01-22

    eLife Sciences Publications, Ltd

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