title: Nova regulates brain-specific splicing to shape the synapse.
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.
authors.affiliation: Howard Hughes Medical Institute and Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA.
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.forename: Aljaz
authors.initials: A
authors.lastname: Ule
authors.forename: Joanna
authors.initials: J
authors.lastname: Spencer
authors.forename: Alan
authors.initials: A
authors.lastname: Williams
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Hu
authors.forename: Melissa
authors.initials: M
authors.lastname: Cline
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Tyson
authors.initials: T
authors.lastname: Clark
authors.forename: Claire
authors.initials: C
authors.lastname: Fraser
authors.forename: Matteo
authors.initials: M
authors.lastname: Ruggiu
authors.forename: Barry R
authors.initials: BR
authors.lastname: Zeeberg
authors.forename: David
authors.initials: D
authors.lastname: Kane
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: John
authors.initials: J
authors.lastname: Blume
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D000090682:Neuro-Oncological Ventral Antigen; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D016601:RNA-Binding Proteins