The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: July 6, 2012

While there are a surprisingly low number of genes in the human genome, 95% of the multi-exonic genes are subject to alternative splicing and therefore the role of alternative splicing in permitting increased cellular and functional complexity should be more widely appreciated.

In different cell types and in response to different conditions, coordinated splicing regulation leads to the specific use of alternative exons and these regulated exon networks can be assumed to play important roles in specific processes and pathways – why else would it occur and be conserved. However, while this regulated behaviour is well known, there is a current lack of understanding of the functional effects imparted by the tissue-regulated alternative exons. A desire to fill in some of this gap motivated the research by a collaborative trio of labs at the University of Toronto. In their Molecular Cell paper, they show that proteins containing regulated exon networks tend to have more interactions in protein-protein interaction networks and that these regulated exons, together with their flanking constitutive exons, are enriched in sequences predicted to be highly disordered.

In a specific example of an alternative exon network regulated by nSR100/SRRM4 (neural-specific Ser/Arg-repeat related protein of 100 kDa), which is responsible for the inclusion of ~11% of brain specific exons, they show that the inclusion of the regulated exons could result in more or fewer protein-protein interactions, depending on the specific gene. Therefore, introduction of a regulated exon and the corresponding additional protein segment does not merely have an additive effect on the range of interactions in which an alternatively spliced protein can engage. Continuing on to a deeper level of detail, the authors show that the inclusion of one of these regulated exons in Bin1 promotes the interaction with the GTPase Dnm2 and that this interaction was needed for efficient endocytosis in neural cells, linking the splicing regulation all the way to cellular function.

Changes in exon splicing are known to be both causes and consequences of multiple human diseases, including tauopathies, spinal muscular atrophy and familial dysautonomia; adding to the functional understanding of alternative splicing will surely allow the identification of more, and the increased chance for the development of a treatment.

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