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Nova regulates brain-specific splicing to shape the synapse
Jernej Ule, Alja Ule, Joanna Spencer, Alan Williams,
Jing-Shan Hu, Melissa Cline, Hui Wang, Tyson Clark, Claire Fraser, Matteo Ruggiu,
Barry R Zeeberg, David Kane, John N Weinstein, John Blume and Robert B Darnell
Nat Genet. 2005 Aug;37(8):844-52. Epub 2005 Jul 24
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Abstract: 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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