Mu Yongxin, Jing Ran, Peter Angela K, Lange Stephan, Lin Lizhu, Zhang Jianlin, Ouyang Kunfu, Fang Xi, Veevers Jennifer, Zhou Xinmin, Evans Sylvia M, Cheng Hongqiang, Chen Ju
Department of Medicine, University of California San Diego, La Jolla, CA (Y.M., R.J., A.K.P., S.L., L.L., J.Z., X.F., J.V., S.M.E., J.C.).
Department of Medicine, University of California San Diego, La Jolla, CA (Y.M., R.J., A.K.P., S.L., L.L., J.Z., X.F., J.V., S.M.E., J.C.) Xiangya Hospital, Central South University, Changsha, China (R.J., X.Z.).
J Am Heart Assoc. 2015 May 5;4(5):e001950. doi: 10.1161/JAHA.115.001950.
The striated muscle Z-line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Cypher and its close homologue, Enigma homolog protein (ENH), are 2 Z-line proteins previously shown to be individually essential for maintenance of postnatal cardiac function and stability of the Z-line during muscle contraction, but dispensable for cardiac myofibrillogenesis and development.
The current studies were designed to test whether Cypher and ENH play redundant roles during embryonic development. Here, we demonstrated that mice lacking both ENH and Cypher exhibited embryonic lethality and growth retardation. Lethality in double knockout embryos was associated with cardiac dilation and abnormal Z-line structure. In addition, when ENH was ablated in conjunction with selective ablation of either Cypher short isoforms (CypherS), or Cypher long isoforms (CypherL), only the latter resulted in embryonic lethality.
Cypher and ENH redundantly play an essential role in sustaining Z-line structure from the earliest stages of cardiac function, and are redundantly required to maintain normal embryonic heart function and embryonic viability.
横纹肌Z线是肌节之间边界处的一种多蛋白复合体，在维持横纹肌结构和功能中发挥着不可或缺的作用。多种与Z线相关的蛋白已被鉴定出来，并显示在人类心肌病的发病机制中发挥着越来越重要的作用。Cypher及其紧密同源物Enigma同源蛋白（ENH）是两种Z线蛋白，先前已证明它们对于维持出生后心脏功能以及肌肉收缩期间Z线的稳定性各自必不可少，但对于心肌原纤维形成和发育并非必需。
当前的研究旨在测试Cypher和ENH在胚胎发育过程中是否发挥冗余作用。在此，我们证明同时缺乏ENH和Cypher的小鼠表现出胚胎致死性和生长迟缓。双敲除胚胎中的致死性与心脏扩张和Z线结构异常有关。此外，当ENH与Cypher短异构体（CypherS）或Cypher长异构体（CypherL）的选择性缺失一起被敲除时，只有后者导致胚胎致死性。
Cypher和ENH在从心脏功能的最早阶段维持Z线结构方面发挥着冗余的重要作用，并且在维持正常胚胎心脏功能和胚胎活力方面也是冗余必需的。
