Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant
Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant
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DOI：
10.1161/hh1301.092497
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发表时间：
2001-07-06
影响因子：
20.1
通讯作者：
Copp, AJ
中科院分区：
文献类型：
--
作者：
Henderson, DJ;Conway, SJ;Copp, AJ
Loop-tail（Lp）是一种自然发生的小鼠突变体，可导致严重的神经管缺陷。在这项研究中，我们描述了复杂的心血管缺陷的脂蛋白纯合子，其中包括双出口右心室，与强制性膜周室间隔缺损，双侧主动脉弓，与相关的异常主动脉弓动脉。流出道和主动脉弓缺陷通常与心脏神经嵴异常有关，但使用分子和解剖学标记，我们表明神经嵴迁移在Lp/Lp胚胎中是正常的。另一方面，在Lp/Lp胚胎中，心脏无法正常成环，与不完全的轴向旋转和颈部屈曲减少有关。因此，心室环相对于其在野生型胚胎中的位置向后内侧移位。这表明在Lp突变体中观察到的心脏排列缺陷可能是继发于神经管闭合失败和轴向旋转不完全。双侧主动脉弓在小鼠模型中是一种罕见的发现。在人类中，它通常是一种孤立的畸形，很少与其他心脏缺陷合并发生。我们认为双侧主动脉弓是Lp突变体的主要缺陷，与排列缺陷无关，可能反映了Lp基因在主动脉弓系统的维持/退化中的作用。
Loop-tail (Lp) is a naturally occurring mouse mutant that develops severe neural tube defects. In this study, we describe complex cardiovascular defects in Lp homozygotes, which include double-outlet right ventricle, with obligatory perimembranous ventricular septal defects, and double-sided aortic arch, with associated abnormalities in the aortic arch arteries. Outflow tract and aortic arch defects are often related to abnormalities in the cardiac neural crest, but using molecular and anatomic markers, we show that neural crest migration is normal in Lp/Lp embryos. On the other hand, the heart fails to loop normally in Lp/Lp embryos, in association with incomplete axial rotation and reduced cervical flexion. As a consequence, the ventricular loop is shifted posteromedially relative to its position in wild-type embryos. This suggests that the observed cardiac alignment defects in the Lp mutant may be secondary to failure of neural tube closure and incomplete axial rotation. Double-sided aortic arch is a rare finding among mouse models. In humans, it is usuary an isolated malformation, only rarely occurring in combination with other cardiac defects. We suggest that the double-sided arch arises as a primary defect in the Lp mutant, unrelated to the alignment defects, perhaps reflecting a role for the las-yet-unknown) Lp gene in maintenance/regression of the aortic arch system.