Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development
Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development
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DOI：
10.1016/s0012-1606(98)80027-4
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发表时间：
1998-06-01
影响因子：
2.7
通讯作者：
Lo, CW
中科院分区：
文献类型：
--
作者：
Huang, GY;Wessels, A;Lo, CW
Cx43基因敲除小鼠和过表达Cx43间隙连接基因的转基因小鼠（CMV 43）表现出涉及圆锥干和右心室的心脏缺陷。基于心脏表型和Cx43基因和转基因表达模式，我们先前提出心脏缺陷可能反映了间隙连接在心脏神经嵴发育调节中的作用。为了进一步阐明这些心脏缺陷可能出现的机制，通过磁共振显微镜和多普勒超声心动图检查这些转基因和基因敲除小鼠的胎儿心脏结构和功能。E14.5胎仔的磁共振显微镜显示，在杂合Cx43基因敲除和CMV 43转基因小鼠中右心室腔扩大。这是伴随着室壁变薄。在纯合子Cx43基因敲除小鼠中，心脏畸形也仅限于右心室。这是一般的特点是两个袋在底部的肺流出道，但偶尔心脏与一个单一的pouch被founded.Magnetic共振显微镜显示，在一些CMV43和Cx43基因敲除小鼠的动脉导管的衰减，这可能是一个表型的流出道阻塞的指示。宫内多普勒超声心动图证实了这一点，显示E12.5至14.5 CMV 43和Cx43基因敲除胎儿的流出速度增加。在其中一些胎仔中，多普勒分析还显示心律失常和等容收缩时间缺失。通过组织学和免疫组织化学进一步检查这些心脏，发现圆锥干中的心肌发育异常。特别令人感兴趣的是存在丰富的内膜下纤维组织表达平滑肌肌动蛋白。在发育中的心脏中，流出道中的这种间充质通常被认为是神经嵴来源的组织。总之，这些结果证实了Cx43基因剂量在圆锥动脉干心脏发育中的重要性，并表明这可能涉及Cx43间隙连接在心脏嵴发育中的作用。在未来的研究中，这些转基因小鼠可以作为有价值的动物模型，进一步研究间隙连接和心脏嵴细胞在圆锥干心脏发育中的作用。(C)北京：科学出版社.
Connexin 43 (Cx43) knockout mice and transgenic mice (CMV43) overexpressing the Cx43 gap junction gene exhibit heart defects involving the conotruncus and right ventricle. Based on the heart phenotype and Cx43 gene and transgene expression pattern, we previously proposed that the heart defects may reflect a role for gap junctions in the modulation of cardiac neural crest development. To further elucidate the mechanism by which these heart defects may arise, fetal heart structure and function in these transgenic and knockout mice were examined by magnetic resonance microscopy and Doppler echocardiography. Magnetic resonance microscopy of E14.5 fetuses revealed an enlargement of the right ventricular chamber in the heterozygous Cx43 knockout and CMV43 transgenic mice. This was accompanied by thinning of the chamber wall. In the homozygous Cx43 knockout mouse, heart malformation was also restricted to the right ventricle. This was generally characterized by two pouches at the base of the pulmonary outflow tract, but occasionally hearts with a single pouch were found. Magnetic resonance microscopy showed in some of the CMV43 and Cx43 knockout mice an attenuation of the ductus arteriosus, a phenotype which may be indicative of outflow tract obstruction. This was confirmed by the in utero Doppler echocardiography, which showed increased outflow velocity in E12.5 to 14.5 CMV43 and Cx43 knockout fetuses. In some of these fetuses, Doppler analysis also revealed arrhythmia and absence of isovolemic contraction time. Further examination of these hearts by histology and immunohistochemistry showed abnormal myocardial development in the conotruncus. Particularly interesting was the presence of abundant subendocardial fibrous tissue expressing smooth muscle actin. In the developing heart, such mesenchyme in the outflow tract is usually considered neural crest-derived tissue. Together, these results confirm the importance of Cx43 gene dosage in conotruncal heart development and suggest that this likely involves a role for Cx43 gap junctions in cardiac crest development. In future studies, these transgenic mice may serve as valuable animal models for further studying the role of gap junctions and cardiac crest cells in conotruncal heart development. (C) 1998 Academic Press.