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. 2015 May 5;4(5):e001950.
doi: 10.1161/JAHA.115.001950.

Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival

Yongxin Mu  1 , Ran Jing  2 , Angela K Peter  1 , Stephan Lange  1 , Lizhu Lin  3 , Jianlin Zhang  1 , Kunfu Ouyang  4 , Xi Fang  1 , Jennifer Veevers  1 , Xinmin Zhou  5 , Sylvia M Evans  3 , Hongqiang Cheng  6 , Ju Chen  1
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Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival

Yongxin Mu et al. J Am Heart Assoc. .

Erratum in

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. VSports手机版.

Methods and 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 V体育安卓版. 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 V体育ios版. .

Keywords: Cypher; Enigma homolog protein; Z‐line; embryonic lethality VSports最新版本. .

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Figures

Figure 1
Figure 1
Cypher and ENH are specifically expressed in the myocardium at E9.5. A through D, Immunofluorescence analysis of a transverse section of the heart of a wild-type embryo at E9.5, staining for (A) DAPI, (B) Cypher, and (C) CD31. D, Color-merged image of DAPI (blue), Cypher (green), and CD31 (red). Arrow, myocardium; arrowhead, endocardium. E and F, Whole-mount RNA in situ hybridization analysis of ENH expression in a wild-type embryo (right and left lateral views) at E9.5 using an ENH-specific probe. G, Histological analysis of a transverse section of the heart from the embryo depicted in (E and F). H, High-magnification view of boxed area in (G). Arrow indicates myocardium; arrowhead, endocardium; DAPI, 4’,6-diamidino-2-phenylindole; ENH, Enigma homolog protein; la, left atrium; lv, left ventricle; ra, right atrium; rv, right ventricle.
Figure 2
Figure 2
ENH−/−/Cypher−/− embryos display aberrant embryonic development and cardiac morphogenesis at E9.5 to E10.5. Whole-mount microscopic assessment of control and ENH−/−/Cypher−/− dKO embryos (right lateral, anterior, and left lateral views) at different developmental stages. A through C, Control embryo and (D through F), somite-matched ENH−/−/Cypher−/− dKO embryo at E9.0. G through I, Control embryo and (J through L), somite-matched dKO embryo at E9.5. M through O, Control embryo and (P through R), dKO embryo at E10.5. dKO indicates double knockout; ENH, Enigma homolog protein.
Figure 3
Figure 3
ENH−/−/Cypher−/− embryos display severe cardiac morphological abnormalities at E9.5. Whole-mount (anterior view) and histological H&E staining analysis of consecutive (1 to 4) transverse sections of the heart of a (A) control embryo, and (B) a somite-matched ENH−/−/Cypher−/− dKO embryo at E9.5. a indicates atrium; avc, atrioventricular canal; bc, bulbus-cordis; bt, bulbus-truncus; dKO, double knockout; ENH, Enigma homolog protein; H&E, hematoxylin and eosin; ot, outflow tract; v, ventricle.
Figure 4
Figure 4
Disorganized Z-lines in ENH−/−/Cypher−/− mouse cardiac muscle. Immunofluorescence analysis of a transverse section of the heart of (A and C) control and (B and D) somite-matched ENH−/−/Cypher−/− dKO embryos at E9.0 to E9.5. Z- and M-lines were stained using antibodies against (A and B) α-actinin, and (C and D) myomesin, respectively. DNA is stained with DAPI (blue). High-magnification views of boxed areas are shown in the inset. E and F, Representative TEM images of a transverse section of the heart of (E) control and (F) somite-matched dKO embryos at E9.5. Z-lines are indicated by arrows. dKO indicates double knockout; DAPI, 4’,6-diamidino-2-phenylindole; ENH, Enigma homolog protein; TEM, transmission electron microscopy.
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