Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish

被引:11
作者
Yang, Jingchun [1 ]
Shah, Sahrish [1 ]
Olson, Timothy M. [2 ,3 ]
Xu, Xiaolei [1 ,2 ]
机构
[1] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, 200 First St SW, Rochester, MN 55905 USA
[2] Mayo Clin, Coll Med, Dept Internal Med, Div Cardiovasc Dis, 200 First St SW, Rochester, MN 55905 USA
[3] Mayo Clin, Coll Med, Div Pediat Cardiol, Dept Pediat & Adolescent Med, 200 First St SW, Rochester, MN 55905 USA
来源
JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE | 2016年 / 3卷 / 01期
关键词
adult zebrafish; cardiomyopathy; gatad1; TALEN; transgenic fish;
D O I
10.3390/jcdd3010006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Animal models have played a critical role in validating human dilated cardiomyopathy (DCM) genes, particularly those that implicate novel mechanisms for heart failure. However, the disease phenotype may be delayed due to age-dependent penetrance. For this reason, we generated an adult zebrafish model, which is a simpler vertebrate model with higher throughput than rodents. Specifically, we studied the zebrafish homologue of GATAD1, a recently identified gene for adult-onset autosomal recessive DCM. We showed cardiac expression of gatad1 transcripts, by whole mount in situ hybridization in zebrafish embryos, and demonstrated nuclear and sarcomeric I-band subcellular localization of Gatad1 protein in cardiomyocytes, by injecting a Tol2 plasmid encoding fluorescently-tagged Gatad1. We next generated gatad1 knock-out fish lines by TALEN technology and a transgenic fish line that expresses the human DCM GATAD1-S102P mutation in cardiomyocytes. Under stress conditions, longitudinal studies uncovered heart failure (HF)-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines. Based on these efforts of studying a gene-based inherited cardiomyopathy model, we discuss the strengths and bottlenecks of adult zebrafish as a new vertebrate model for assessing candidate cardiomyopathy genes.
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页数:18
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