CRISPR/Cas9-mediated Nexilin deficiency interferes with cardiac contractile function in zebrafish in vivo
Nexilin (NEXN) plays a crucial role in stabilizing the sarcomeric Z-disk of striated muscle fibers and, when mutated,  leads to dilated cardiomyopathy in humans. Due to its early neonatal lethality in mice, the detailed impact of the  constitutive homozygous NEXN knockout on heart and skeletal muscle morphology and function is insufficiently investigated.  We characterized a constitutive homozygous CRISPR/Cas9-mediated nexn knockout zebrafish model. We found that Nexn deficient embryos developed significantly reduced cardiac contractility and under stressed conditions also impaired  skeletal muscle organization whereas skeletal muscle function seemed not to be affected. Remarkably, in contrast to nexn  morphants, CRISPR/Cas9 nexn-/- knockout embryos showed a milder phenotype without the development of a pronounced  pericardial edema or blood congestion. nexn-specific expression analysis as well as whole transcriptome profiling suggest  some degree of compensatory mechanisms. Transcripts of numerous essential sarcomeric proteins were massively induced  and may mediate a sarcomere stabilizing function in nexn-/- knockout embryos. Overall design: To investigate the influence of nexn knockout on cardiac and skeletal muslce, we generated a CRISPR/Cas9-mediated nexn  knockout zebrafish model. We then performed gene expression profiling analysis using data obtained from RNA-seq.