title: RNA splicing regulated by RBFOX1 is essential for cardiac function in zebrafish.
abstract: Alternative splicing is one of the major mechanisms through which the proteomic and functional diversity of eukaryotes is achieved. However, the complex nature of the splicing machinery, its associated splicing regulators and the functional implications of alternatively spliced transcripts are only poorly understood. Here, we investigated the functional role of the splicing regulator rbfox1 in vivo using the zebrafish as a model system. We found that loss of rbfox1 led to progressive cardiac contractile dysfunction and heart failure. By using deep-transcriptome sequencing and quantitative real-time PCR, we show that depletion of rbfox1 in zebrafish results in an altered isoform expression of several crucial target genes, such as actn3a and hug. This study underlines that tightly regulated splicing is necessary for unconstrained cardiac function and renders the splicing regulator rbfox1 an interesting target for investigation in human heart failure and cardiomyopathy.
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Frese
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Chair for Clinical Bioinformatics, Saarland University, D-66123 Saarbrücken, Germany Department of Human Genetics, Saarland University, D-66123 Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
authors.affiliation: Department of Medicine II, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Haas
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Vogel
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Human Genetics, Saarland University, D-66123 Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Backes
authors.affiliation: Comprehensive Biomarker Center, D-69120 Heidelberg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Matzas
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Köhler
authors.affiliation: EMBL, European Molecular Biology Laboratory, Genomics Core Facility, D-69117 Heidelberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.affiliation: Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Medicine II, University of Ulm, D-89081 Ulm, Germany wolfgang.rottbauer@uniklinik-ulm.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009479:Neuropeptides / Q000235:genetics; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: D009479:Neuropeptides; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D000185:Actinin
keywords: Deep sequencing; Dilated cardiomyopathy; Genetics; Splicing; Zebrafish