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Global analysis of alternative splicing regulation by insulin and wingless signaling in Drosophila cells

Britta Hartmann12*, Robert Castelo23, Marco Blanchette46, Stephanie Boue127, Donald C Rio4 and Juan Valcárcel125*

Author Affiliations

1 Centre de Regulació Genòmica, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona, 08003, Spain

2 Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona, 08003, Spain

3 Institut Municipal D'Investigació Mèdica, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona, 08003, Spain

4 Department of Molecular and Cell Biology, University of California, Berkeley, 94720, USA

5 Institució Catalana de Recerca i Estudis Avançats, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona, 08003, Spain

6 Current address: Stowers Institute for Medical Research, E. 50th Street, Kansas City, 64110, USA

7 Current address: Centre de Medicina Regenerativa de Barcelona, Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, Barcelona, 08003, Spain

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Genome Biology 2009, 10:R11  doi:10.1186/gb-2009-10-1-r11

Published: 29 January 2009

Abstract

Background

Despite the prevalence and biological relevance of both signaling pathways and alternative pre-mRNA splicing, our knowledge of how intracellular signaling impacts on alternative splicing regulation remains fragmentary. We report a genome-wide analysis using splicing-sensitive microarrays of changes in alternative splicing induced by activation of two distinct signaling pathways, insulin and wingless, in Drosophila cells in culture.

Results

Alternative splicing changes induced by insulin affect more than 150 genes and more than 50 genes are regulated by wingless activation. About 40% of the genes showing changes in alternative splicing also show regulation of mRNA levels, suggesting distinct but also significantly overlapping programs of transcriptional and post-transcriptional regulation. Distinct functional sets of genes are regulated by each pathway and, remarkably, a significant overlap is observed between functional categories of genes regulated transcriptionally and at the level of alternative splicing. Functions related to carbohydrate metabolism and cellular signaling are enriched among genes regulated by insulin and wingless, respectively. Computational searches identify pathway-specific sequence motifs enriched near regulated 5' splice sites.

Conclusions

Taken together, our data indicate that signaling cascades trigger pathway-specific and biologically coherent regulatory programs of alternative splicing regulation. They also reveal that alternative splicing can provide a novel molecular mechanism for crosstalk between different signaling pathways.