The Fox-1 family and SUP-12 coordinately regulate tissue-specific alternative splicing in vivo.
Many pre-mRNAs are alternatively spliced in a tissue-specific manner in multicellular organisms. The Fox-1 family of RNA-binding proteins regulate alternative splicing by either activating or repressing exon inclusion through specific binding to UGCAUG stretches. However, the precise cellular contexts that determine the action of the Fox-1 family in vivo remain to be elucidated. We have recently demonstrated that ASD-1 and FOX-1, members of the Fox-1 family in Caenorhabditis elegans, regulate tissue-specific alternative splicing of the fibroblast growth factor receptor gene, egl-15, which eventually determines the ligand specificity of the receptor in vivo. Here we report that another RNA-binding protein, SUP-12, coregulates the egl-15 alternative splicing. By screening for mutants defective in the muscle-specific expression of our alternative splicing reporter, we identified the muscle-specific RNA-binding protein SUP-12. We identified juxtaposed conserved stretches as the cis elements responsible for the regulation. The Fox-1 family and the SUP-12 proteins form a stable complex with egl-15 RNA, depending on the cis elements. Furthermore, the asd-1; sup-12 double mutant is defective in sex myoblast migration, phenocopying the isoform-specific egl-15(5A) mutant. These results establish an in vivo model that coordination of the two families of RNA-binding proteins regulates tissue-specific alternative splicing of a specific target gene.
Kuroyanagi
Hidehito
H
School of Biomedical Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan. kuroyana.end@tmd.ac.jp
Ohno
Genta
G
Mitani
Shohei
S
Hagiwara
Masatoshi
M
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D017238:Genes, Helminth; D017930:Genes, Reporter; D007438:Introns; D009132:Muscles / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
C515945:Asd-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C112493:EGL-15 protein, C elegans; C117552:FOX-1 protein, C elegans; D016601:RNA-Binding Proteins; D017468:Receptors, Fibroblast Growth Factor; C525043:Sup-12 protein, C elegans