Alternative Splicing Regulation of Cancer-Related Pathways in Caenorhabditis elegans: An In Vivo Model System with a Powerful Reverse Genetics Toolbox

Abstract

Alternative splicing allows for the generation of protein diversity and fine-tunes gene expression. Several model systems have been used for the in vivo study of alternative splicing. Here we review the use of the nematode Caenorhabditis elegans to study splicing regulation in vivo. Recent studies have shown that close to 25% of genes in the worm genome undergo alternative splicing. A big proportion of these events are functional, conserved, and under strict regulation either across development or other conditions. Several techniques like genome-wide RNAi screens and bichromatic reporters are available for the study of alternative splicing in worms. In this review, we focus, first, on the main studies that have been performed to dissect alternative splicing in this system and later on examples from genes that have human homologs that are implicated in cancer. The significant advancement towards understanding the regulation of alternative splicing and cancer that the C. elegans system has offered is discussed.

Figure 1

Caenorhabditis elegans alternative splicing events. (a) Genome-wide analysis of alternative splicing in C. elegans; (b) comparison of the human APAF1 and the C. elegans homolog ced-4 gene models shows significant differences in intron size between species for genes with important alternative splicing events; (c) Y48C3A.5 intron 4 (19,927 bp) is one example of the 144 introns in the C. elegans genome that are more than 10 kb in length; (d) C. elegans unc-52 gene undergoes complex alternative splicing that generates at least 12 different isoforms by the use of nine different cassette exons.

Figure 2

Connections between alternative splicing in C. elegans and pathways homologous to those that cause excessive cell proliferation or apoptosis in humans, as reviewed in this paper.