Understanding Cardiac Sarcomere Assembly With Zebrafish Genetics

Abstract

Mutations in sarcomere genes have been found in many inheritable human diseases, including hypertrophic cardiomyopathy. Elucidating the molecular mechanisms of sarcomere assembly shall facilitate understanding of the pathogenesis of sarcomere-based cardiac disease. Recently, biochemical and genomic studies have identified many new genes encoding proteins that localize to the sarcomere. However, their precise functions in sarcomere assembly and sarcomere-based cardiac disease are unknown. Here, we review zebrafish as an emerging vertebrate model for these studies. We summarize the techniques offered by this animal model to manipulate genes of interest, annotate gene expression, and describe the resulting phenotypes. We survey the sarcomere genes that have been investigated in zebrafish and discuss the potential of applying this in vivo model for larger-scale genetic studies.

The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes

“…Approximately 72% of MG132-treated ncx1h mutants had a striated α-actinin pattern, indicating the presence of intact sarcomeres (n = 18; p<0.001) ( Figure 5A,B ), suggesting that upregulation of MuRF1 induces myofibril degradation via a proteasome-dependent mechanism in ncx1h -deficient cardiomyocytes. Prior studies have implied a connection between cardiac contraction and myofibril integrity ( Berdougo et al, 2003 ; Auman et al, 2007 ; Nishii et al, 2008 ; Yang et al, 2014 ). Interestingly, ncx1h/murf1a/murf1b triple-deficient hearts never establish coordinated contractions ( Video 3 ), demonstrating that sarcomere integrity can be uncoupled from the loss of cardiac contractions in the context of aberrant Ca 2+ handling-induced heart failure.…”

Exon- and contraction-dependent functions of titin in sarcomere assembly

“…Zebrafish is a new vertebrate model for studying sarcomere assembly (Schoenebeck and Yelon, 2007;Huang et al, 2009;Sanger et al, 2009;Yang et al, 2014b). From a large-scale screen using N-ethyl-N-nitrosourea as a mutagen, a group of ttn mutants, named pickwick ( pik), have been identified (Xu et al, 2002).…”

The Role of Cardiac Myosin Binding Protein C3 in Hypertrophic Cardiomyopathy‐Progress and Novel Therapeutic Opportunities

“…Zebrafish ( Danio rerio ), a tropical freshwater fish, has recently emerged as an ideal vertebrate animal system for investigating mechanisms of cardiac development and human CHDs (Poon and Brand, ). The ability of zebrafish mutant embryos to survive without a functional circulation system for several days further emphasizes the feasibility of carrying out gain‐of‐function and loss‐of‐function studies in zebrafish (Yang et al, ).…”