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首页> 外文期刊>Molecular and Cellular Biology >The W-Loop of Alpha-Cardiac Actin Is Critical for Heart Function and Endocardial Cushion Morphogenesis in Zebrafish
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The W-Loop of Alpha-Cardiac Actin Is Critical for Heart Function and Endocardial Cushion Morphogenesis in Zebrafish

机译：阿尔法心脏肌动蛋白的W循环对于斑马鱼的心功能和心内膜垫形态发生至关重要

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Mutations in cardiac actin (ACTC) have been associated with different cardiac abnormalities in humans, including dilated cardiomyopathy and septal defects. However, it is still poorly understood how altered ACTC structure affects cardiovascular physiology and results in the development of distinct congenital disorders. A zebrafish mutant (s434 mutation) was identified that displays blood regurgitation in a dilated heart and lacks endocardial cushion (EC) formation. We identified the mutation as a single nucleotide change in the alpha-cardiac actin 1a gene (actc1a), resulting in a Y169S amino acid substitution. This mutation is located at the W-loop of actin, which has been implicated in nucleotide sensing. Consequently, s434 mutants show loss of polymerized cardiac actin. An analogous mutation in yeast actin results in rapid depolymerization of F-actin into fragments that cannot reanneal. This polymerization defect can be partially rescued by phalloidin treatment, which stabilizes F-actin. In addition, actc1a mutants show defects in cardiac contractility and altered blood flow within the heart tube. This leads to downregulation or mislocalization of EC-specific gene expression and results in the absence of EC development. Our study underscores the importance of the W-loop for actin functionality and will help us to understand the structural and physiological consequences of ACTC mutations in human congenital disorders.
机译：心脏肌动蛋白（ACTC）的突变与人类不同的心脏异常有关，包括扩张型心肌病和间隔缺损。然而，人们仍然不太了解ACTC结构的变化如何影响心血管生理学并导致明显的先天性疾病的发展。鉴定出斑马鱼突变体（ s434 突变），该突变体在扩张的心脏中显示出血液反流，并且缺乏心内膜垫（EC）的形成。我们确定该突变为α-心脏肌动蛋白1a基因（ actc1a ）中的单个核苷酸变化，从而导致Y169S氨基酸取代。该突变位于肌动蛋白的W-环，其与核苷酸感测有关。因此， s434 突变体显示聚合的肌动蛋白丢失。酵母肌动蛋白中的类似突变导致F-肌动蛋白迅速解聚为无法重新退火的片段。通过鬼笔环肽处理可以部分挽救该聚合缺陷，从而稳定F-肌动蛋白。此外， actc1a 突变体显示出心脏收缩力缺陷和心管内血流改变。这会导致EC特异性基因表达的下调或定位错误，并导致EC发育缺失。我们的研究强调了W环对肌动蛋白功能的重要性，并将帮助我们了解人类先天性疾病中ACTC突变的结构和生理后果。

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