RNA splicing regulated by RBFOX1 is essential for cardiac function in zebrafish

Abstract

Alternative splicing (AS) is one of the major mechanisms to warrant the proteomic and functional diversity of eukaryotes. However, the complex nature of the splicing machinery, its associated splicing regulators and the functional implications of alternatively spliced transcripts is only poorly understood. We investigated here the functional role of the splicing regulator rbfox1 in vivo using the zebrafish as a model system. We find that loss-of rbfox1 leads 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 to be investigated in human heart failure and cardiomyopathy.