title: An alternative splicing event amplifies evolutionary differences between vertebrates.
abstract: 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.
authors: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Serge
authors: S
authors: Gueroussov
authors: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors: Thomas
authors: T
authors: Gonatopoulos-Pournatzis
authors: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain.
authors: Manuel
authors: M
authors: Irimia
authors: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Bushra
authors: B
authors: Raj
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors: Zhen-Yuan
authors: ZY
authors: Lin
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors: Anne-Claude
authors: AC
authors: Gingras
authors: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. b.blencowe@utoronto.ca.
authors: Benjamin J
authors: BJ
authors: Blencowe
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000196:embryology*; D002645:Chickens; D053595:Embryonic Stem Cells / Q000378:metabolism; D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics*
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; C450006:PTBP1 protein, human; C573992:Ptbp1 protein, mouse; D038941:Polypyrimidine Tract-Binding Protein