Angel wing: a class of alternative splicing regulators in animals.

Abstract

Alternative splicing (AS) regulates the diversity and level of the proteome. The specificity in AS is in turn regulated by RNA-binding proteins, but our understanding of how they act is far from complete. Here, we identify the Angel wing (Anw) protein, previously CG10948, as a novel AS regulator. Loss of Anw in Drosophila disrupts splicing in muscle genes and subsequently muscle function. Based on a mini-gene assay in which Anw and its RNA targets are co-expressed in cultured cells, we demonstrated orthologous splicing regulation of the mini-gene transcripts, interaction between Anw and its RNA targets, and a remarkable functional conservation among Anw homologs. Anw forms nuclear foci, and genetic ablation of Anw domains suggests that maintaining distinctive features of these foci is important for its function. The evolution of Anw is dynamic with gene gains and losses, but as others suggested, preserves a cross-phyla "ultra conserved element" as an alternative exon that potentially regulates its own level by nonsense-mediated mRNA decay. As the human anw homolog is a candidate gene for myasthenia gravis, our work suggests a mechanism for cellular dysfunction in this disease.