An alternative splicing event amplifies evolutionary differences between vertebrates

Regulation of splicing regulators The messenger RNAs of most eukaryotic genes are formed by splicing together a series of exons and removing the intervening introns. The identity and order of the exons can vary between mRNAs for the same gene. The alternatively spliced products can generate an increased diversity of protein products. Gueroussov et al. show that the alternative splicing of a mammalian splicing regulatory factor affects, in turn, the alternative splicing of a wide range of target RNAs. This regulation mechanism controls a brain-specific alternative splicing program. Science, this issue p. 868 Altered splicing of a splicing regulator activates brain-specific alternative splicing. Alternative splicing (AS) generates extensive transcriptomic and proteomic complexity. However, the functions of species- and lineage-specific splice variants are largely unknown. Here we show that mammalian-specific skipping of polypyrimidine tract–binding protein 1 (PTBP1) exon 9 alters the splicing regulatory activities of PTBP1 and affects the inclusion levels of numerous exons. During neurogenesis, skipping of exon 9 reduces PTBP1 repressive activity so as to facilitate activation of a brain-specific AS program. Engineered skipping of the orthologous exon in chicken cells induces a large number of mammalian-like AS changes in PTBP1 target exons. These results thus reveal that a single exon-skipping event in an RNA binding regulator directs numerous AS changes between species. Our results further suggest that these changes contributed to evolutionary differences in the formation of vertebrate nervous systems.