title: TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy.
abstract: Prevention of skipping of exon 7 during pre-mRNA splicing of Survival Motor Neuron 2 (SMN2) holds the promise for cure of spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Here, we report T-cell-restricted intracellular antigen 1 (TIA1) and TIA1-related (TIAR) proteins as intron-associated positive regulators of SMN2 exon 7 splicing. We show that TIA1/TIAR stimulate exon recognition in an entirely novel context in which intronic U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. TIA1 and TIAR are modular proteins with three N-terminal RNA recognition motifs (RRMs) and a C-terminal glutamine-rich (Q-rich) domain. Our results reveal that any one RRM in combination with a Q domain is necessary and sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. We also show that increased expression of TIA1 counteracts the inhibitory effect of polypyrimidine tract binding protein, a ubiquitously expressed factor recently implicated in regulation of SMN exon 7 splicing. Our findings expand the scope of TIA1/TIAR in genome-wide regulation of alternative splicing under normal and pathological conditions.
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, 2034 Veterinary Medicine Bldg., Iowa State University, Ames, IA 50011, USA. singhr@iastate.edu
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Singh
authors.forename: Joonbae
authors.initials: J
authors.lastname: Seo
authors.forename: Eric W
authors.initials: EW
authors.lastname: Ottesen
authors.forename: Maria
authors.initials: M
authors.lastname: Shishimorova
authors.forename: Dhruva
authors.initials: D
authors.lastname: Bhattacharya
authors.forename: Ravindra N
authors.initials: RN
authors.lastname: Singh
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D005091:Exons; D006801:Humans; D007438:Introns; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D038941:Polypyrimidine Tract-Binding Protein / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D038941:Polypyrimidine Tract-Binding Protein; C076751:TIAL1 protein, human