Nature Genetics
37, 844 - 852 (2005)
Published online: 24 July 2005; | doi:10.1038/ng1610
Nova regulates brain-specific splicing to shape the synapseJernej Ule1, Alja Ule2, Joanna Spencer1, Alan Williams3, Jing-Shan Hu3, Melissa Cline3, Hui Wang3, Tyson Clark3, Claire Fraser1, Matteo Ruggiu1, Barry R Zeeberg4, David Kane5, John N Weinstein4, John Blume3
& Robert B Darnell11
Howard Hughes Medical Institute and Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. 2
Faculty of Economics and Econometrics, University of Amsterdam, Netherlands. 3
Affymetrix Inc., 6550 Vallejo Street, Suite 100, Emeryville, California, USA. 4
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 5
SRA International Inc., 4300 Fair Lakes Ct., Fairfax, Virginia 22033, USA.
Correspondence should be addressed to Robert B Darnell darnelr@rockefeller.edu Alternative RNA splicing greatly increases proteome diversity and may thereby contribute to tissue-specific functions. We carried out genome-wide quantitative analysis of alternative splicing using a custom Affymetrix microarray to assess the role of the neuronal splicing factor Nova in the brain. We used a stringent algorithm to identify 591 exons that were differentially spliced in the brain relative to immune tissues, and 6.6% of these showed major splicing defects in the neocortex of Nova2-/- mice. We tested 49 exons with the largest predicted Nova-dependent splicing changes and validated all 49 by RT-PCR. We analyzed the encoded proteins and found that all those with defined brain functions acted in the synapse (34 of 40, including neurotransmitter receptors, cation channels, adhesion and scaffold proteins) or in axon guidance (8 of 40). Moreover, of the 35 proteins with known interaction partners, 74% (26) interact with each other. Validating a large set of Nova RNA targets has led us to identify a multi-tiered network in which Nova regulates the exon content of RNAs encoding proteins that interact in the synapse.
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