Functional redundancy Sample Clauses

Functional redundancy among CELF protein family members A prominent splicing target for CELF proteins is Cardiac troponin T (cTNT). The alternative splicing pattern of cTNT is developmentally regulated and conserved from birds to mammals (Xxxx et al., 2001). The alternative cTNT exon 5 which is normally included in the embryo of cardiac and skeletal muscle is skipped in adult cardiac muscle mRNA (Xxxx et al., 2001) (Xxxxxxx et al., 2006). Alternative splicing of cTNT exon 5 generates isoforms with different contractive properties important during muscle development (Xxxxxx and Ordahl, 1985). All CELF proteins bind to conserved intronic elements called muscle-specific splicing enhancer elements (MSEs) which contains a CUG repeat to promote exon 5 inclusion (Xxxx et al., 2001). Although this splicing event is dependent on different intronic splicing enhancer (ISE) elements, CELF3 and CELF6 promote exon 5 inclusion in the presence of a muscle-specific ISE element (MSE2) found at the proximal region flanking exon 5 while other CELF proteins require several MSE elements (Xxxx et al., 2001). Furthermore, all regions within CELF proteins are implicated in the splicing regulation of cTNT exon 5. These include sequences within RRM1 and RRM2 of CELF2 as well as regions within the divergent domain and RRM1 of CELF4 (Xxxxx et al., 2004). Altogether, these findings suggest that different ISE elements in addition to domains within CELF proteins are indispensable for splicing activity of the same exon which indicates functional redundancy among CELF family members. An orthologue of CELF3, 4 and 5 in Caenorhabditis elegans, unc-75, is neuron specific and involved in neurotransmission where it regulates neuron-specific alternative splicing (Xxxxx et al., 2003). unc-75 null mutants have a motor phenotype that is rescued by human CELF4 (Xxxxx et al., 2003). These studies illustrate the importance of CELF proteins in maintaining neuronal function. Similarly, the generation of mouse models deficient in specific CELF proteins, has helped to elucidate the role of members of the CELF family during alternative splicing. In mice lacking CELF1, growth is retarded; there is impaired viability and reduced fertility due to disruption of spermatogenesis (Xxxxx et al., 2007). CELF3 knock-out mice did not show any reduction in fertility but similar to CELF1 knock-out mice, they have reduced spermatogenesis (Xxx et al., 2007). This may be the result of the compensatory effect of other members of the CELF family...