Article
- The EMBO Journal (2005) 24, 1608 - 1620
- doi:10.1038/sj.emboj.7600630
Published online: 31 March 2005
Subject Categories:
Nova autoregulation reveals dual functions in neuronal splicing
B Kate Dredge1,a, Giovanni Stefani1, Caitlin C Engelhard1 and Robert B Darnell1
- Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA
Correspondence to:
Robert B Darnell, Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. Tel.: +1 212 327 7460; Fax: +1 212 327 7109; E-mail: darnelr@rockefeller.edu
aPresent address: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia
Received 10 November 2004; Accepted 23 February 2005
Abstract
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 GABAAR
2 and GlyR
2 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 GABAAR2 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.
Keywords:
- alternative splicing,
- exonic splicing silencer,
- KH domain,
- neuron specific,
- RNA-binding protein
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