CRISPR/Cas9-mediated nexilin deficiency interferes with cardiac contractile function in zebrafish in vivo
Year: 2023
Type: article
Abstract: 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. Here, 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. Our findings demonstrate the successful generation and characterization of a constitutive homozygous nexn knockout line enabling the detailed investigation of the role of nexn on heart and skeletal muscle development and function as well as to assess putative compensatory mechanisms induced by the loss of Nexn.
Source: Scientific Reports
Authors: Janessa Hofeichner, Bernd Martin Gahr, Magdalena Huber, Alena Boos, Wolfgang Rottbauer, Steffen Just
Institution: Universität Ulm
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,390
Awards: Juniorverbünde in der Systemmedizin: Funktionelle Genomik im Zebrafisch zur Aufklärung molekularer Netzwerke der Herzinsuffizienz und Modellanalyse der Herzinsuffizienz (SYMBOL-HF), Universität Ulm, G5553022360, coNfirm - Netzwerke der Herzerkrankungen. Systemmedizinischer Ansatz zur Verbesserung der Herzgesundheit - Multi-spezies und multi-level Daten Ressource (TP1) und Bioinformatische Ansätze zur Generierung von gemeinsamen Signalwegen kardialer Erkrankungen (TP2), G772031190
OpenAlex ID: W4389946635