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Exon silencing by UAGG motifs in response to neuronal excitation

An, P and Grabowski, PJ (2007) Exon silencing by UAGG motifs in response to neuronal excitation. PLoS Biology, 5 (2). 0263 - 0280. ISSN 1544-9173

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Abstract

Alternative pre-mRNA splicing plays fundamental roles in neurons by generating functional diversity in proteins associated with the communication and connectivity of the synapse. The CI cassette of the NMDA R1 receptor is one of a variety of exons that show an increase in exon skipping in response to cell excitation, but the molecular nature of this splicing responsiveness is not yet understood. Here we investigate the molecular basis for the induced changes in splicing of the CI cassette exon in primary rat cortical cultures in response to KCl-induced depolarization using an expression assay with a tight neuron-specific readout. In this system, exon silencing in response to neuronal excitation was mediated by multiple UAGG-type silencing motifs, and transfer of the motifs to a constitutive exon conferred a similar responsiveness by gain of function. Biochemical analysis of protein binding to UAGG motifs in extracts prepared from treated and mock-treated cortical cultures showed an increase in nuclear hnRNP A1-RNA binding activity in parallel with excitation. Evidence for the role of the NMDA receptor and calcium signaling in the induced splicing response was shown by the use of specific antagonists, as well as cell-permeable inhibitors of signaling pathways. Finally, a wider role for exon-skipping responsiveness is shown to involve additional exons with UAGG-related silencing motifs, and transcripts involved in synaptic functions. These results suggest that, at the post-transcriptional level, excitable exons such as the CI cassette may be involved in strategies by which neurons mount adaptive responses to hyperstimulation. © 2007 An and Grabowski.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
An, Ppia1@pitt.eduPIA10000-0002-3080-2288
Grabowski, PJpag4@pitt.eduPAG40000-0003-1881-6190
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorWickens, MarvUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 February 2007
Date Type: Publication
Journal or Publication Title: PLoS Biology
Volume: 5
Number: 2
Page Range: 0263 - 0280
DOI or Unique Handle: 10.1371/journal.pbio.0050036
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Refereed: Yes
ISSN: 1544-9173
PubMed ID: 17298175
Date Deposited: 11 Jul 2012 17:27
Last Modified: 02 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/12858

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