Nova autoregulation reveals dual functions in neuronal splicing

The Nova family of neuron‐specific RNA‐binding proteins were originally identified as targets in an autoimmune neurologic disease characterized by failure of motor inhibition. Nova‐1 regulates alternative splicing of pre‐mRNAs encoding the inhibitory neurotransmitter receptor subunits GABAARγ2 and GlyRα2 by directly binding intronic elements, resulting in enhancement of exon inclusion. Here we identify exon E4 in the Nova‐1 pre‐mRNA itself, encoding a phosphorylated protein domain, as an additional target of Nova‐dependent splicing regulation in the mouse spinal cord. Nova binding to E4 is necessary and sufficient for Nova‐dependent exon exclusion. E4 harbors five repeats of the known Nova‐binding tetranucleotide YCAY and mutation of these elements destroys Nova‐dependent regulation. Furthermore, swapping of the sites from Nova‐1 and GABAARγ2 indicates that the ability of Nova to enhance or repress alternative exon inclusion is dependent on the position of the Nova‐binding element within the pre‐mRNA. These studies demonstrate that in addition to its previously described role as a splicing activator, Nova autoregulates its own expression by acting as a splicing repressor.

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