Functional consequences of developmentally regulated alternative splicing

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Abstract
A large fraction of genes in worms, flies and vertebrates express multiple mRNAs by alternative splicing. This produces extensive mRNA structural diversity that ultimately affects protein coding potential as well as mRNA cis-acting elements that are determinative for translation, mRNA stability and mRNA intracellular localization. Global analyses of alternative splicing regulation during periods of biological transition, such as during development, have revealed coordinated and conserved networks of alternative splicing. Several splicing regulatory networks controlled by individual RNA-binding proteins have been identified by combining recent advances in genome-wide analyses of alternative splicing with the identification of RNA binding sites in vivo. A high proportion of RNA-binding proteins that regulate alternative splicing are themselves regulated by alternative splicing and are subject to auto- and crossregulatory feedback. This type of regulation includes alternative splicing linked with nonsense-mediated decay (AS–NMD), which results in mRNA downregulation. Diverse physiological processes are regulated in a determinative fashion by alternative splicing patterns, including meiosis in budding yeast, neuronal arborization in the Drosophila melanogaster brain, and stem cell determination in vertebrates. The regulation of gene expression by alternative splicing is intricately linked with transcription, the epigenetic state of chromatin, and subsequent RNA processing events, such as 3′ end formation, mRNA export and mRNA translation efficiency.