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Discovery of Tra2b splicing factor in a novel pathway regulating vascular smooth phenotypic diversity
Author(s) -
Fisher Steven A,
Shukla Supriya
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.744.11
Subject(s) - exon , rna splicing , biology , minigene , phenotype , alternative splicing , genetics , splicing factor , gene , exon skipping , microbiology and biotechnology , rna
We are using the regulated splicing of Myosin Phosphatase Targeting subunit 1 (MYPT1) 3′ alternative exon (altex) as a model for the study of vascular smooth muscle (VSM) phenotypic diversity. This exon is skipped in aorta and other large vessels and spliced in the mesenteric resistance artery and portal vein. The splicing modulates in disease models of altered flow and in development. The control mechanisms for the generation of VSM phenotypic diversity are unknown. We identified a consensus binding site for the splicing factor Tra2β (Transformer) 1 in the MYPT1 alt exon. Tra in flies specifies female phenotype by its ability to enhance splicing of a Doublesex altex. The expression of Tra2β correlated precisely with MYPT1 exon inclusion in developmental and disease models, while expressions of other SR family members did not. Tra2β bound to the MYPT1 altexon, and was able to trans‐activate altex splicing from a mini‐gene construct in co‐transfection assays. Mutation or deletion of the Tra2β binding site abrogated these activities. We conclude that Tra2β represents a novel pathway for the activation of the fast (phasic) program of gene expression in the generation of VSM phenotypic diversity. (Support: NIH HL66171 (to S.A.F.)