Depletion of zebrafish essential and regulatory myosin light chains reduces cardiac function through distinct mechanisms
Depletion of zebrafish essential and regulatory myosin light chains reduces cardiac function through distinct mechanisms
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DOI：
10.1093/cvr/cvn073
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发表时间：
2008-07-01
影响因子：
10.8
通讯作者：
Xu, Xiaolei
中科院分区：
文献类型：
--
作者：
Chen, Zhenyue;Huang, Wei;Xu, Xiaolei
目的：必需肌球蛋白轻链（ELC）和调节性肌球蛋白轻链（RLC）基因的突变与人类肌瘤性肥厚性心肌病有关；然而，不同的肌球蛋白轻链在脊椎动物心脏发生过程中的具体功能尚不清楚。方法与结果以斑马鱼（Danio rerio）为模型生物，分别鉴定出cmlc1和cmlc2为主要的ELC和RLC同源物，并利用形态学技术进一步表征了它们在心脏发生过程中的功能。使用morpholino修饰的反义寡核苷酸耗尽cmlc1或cmlc2都会导致肌节结构的破坏并损害心功能，尽管其机制似乎不同。虽然在两种变形体中肌凝蛋白仍然组装成一种新的杆状结构，但cmlc1型的肌节长度比野生型的更长，而cmlc2型的更短。此外，cmlc1耗尽后心肌细胞的大小和数量增加，导致心室容积增大；相反，cmlc2的缺失导致心肌细胞大小和数量的减少。我们的数据阐明了cmlc1和cmlc2在斑马鱼心脏发生过程中的不同作用，表明人类ELCs与rlc突变引起的心肌病在疾病进展过程中可能具有不同的病理特征。
Aims Mutations in the essential myosin light chain (ELC) and regulatory myosin light chain (RLC) genes have been linked to sarcomeric hypertrophic cardiomyopathies in humans; however, the specific functions of the different myosin light chains during cardiogenesis in a vertebrate animal are not well understood.Methods and results Using zebrafish (Danio rerio) as a model organism, we have identified cmlc1 and cmlc2 as the main ELC and RLC orthologues, respectively, and have furthermore characterized their functions during cardiogenesis by morpholino technology. Depletion of either cmlc1 or cmlc2 using morpholino-modified antisense oligonucleotides leads to a disruption in sarcomere structure and compromises cardiac function as well, although through seemingly distinct mechanisms. While myosin still assembles into a novel rod-like structure in both morphants, the sarcomere length is longer in cmlc1 morphants than that in wild-type embryos, whereas it is shorter in cmlc2 morphants. In addition, cardiomyocyte size and number are increased upon depletion of cmlc1, resulting in a larger ventricular chamber volume; in contrast, depletion of cmlc2 leads to a reduction in cardiomyocyte size and number.Conclusion Our data have elucidated distinct roles for cmlc1 and cmlc2 during zebrafish cardiogenesis, suggesting that cardiomyopathies resulting from human mutations in ELCs vs. RLCs may have distinct pathological characteristics during disease progression.