title: Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.).
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Mu
authors.affiliation: 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.).
authors.forename: Ran
authors.initials: R
authors.lastname: Jing
authors.affiliation: 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.).
authors.forename: Angela K
authors.initials: AK
authors.lastname: Peter
authors.affiliation: 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.).
authors.forename: Stephan
authors.initials: S
authors.lastname: Lange
authors.affiliation: 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, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA (L.L., S.M.E.).
authors.forename: Lizhu
authors.initials: L
authors.lastname: Lin
authors.affiliation: 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.).
authors.forename: Jianlin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Chemical Genomics, Drug Discovery Center, Peking University Shenzhen Graduate School, Shenzhen, China (K.O.).
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.affiliation: 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.).
authors.forename: Xi
authors.initials: X
authors.lastname: Fang
authors.affiliation: 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.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Veevers
authors.affiliation: Xiangya Hospital, Central South University, Changsha, China (R.J., X.Z.).
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA (L.L., S.M.E.).
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China (H.C.).
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.affiliation: 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.).
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D060588:LIM Domain Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D054792:Muscle, Striated / Q000002:abnormalities* / Q000254:growth & development*; D009206:Myocardium / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510085:ENH protein, mouse; D060588:LIM Domain Proteins; C485639:Ldb3 protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms
keywords: Cypher; Enigma homolog protein; Z‐line; embryonic lethality