Bradshaw Lucy, Chaudhry Bill, Hildreth Victoria, Webb Sandra, Henderson Deborah J
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
J Anat. 2009 Feb;214(2):245-57. doi: 10.1111/j.1469-7580.2008.01028.x.
Splotch(2H) (Sp(2H)) is a well-recognized mouse model of neural crest cell (NCC) deficiency that develops a spectrum of cardiac outflow tract malformations including common arterial trunk, double outlet right ventricle, ventricular septal defects and pharyngeal arch artery patterning defects, as well as defects in other neural-crest derived organ systems. These defects have been ascribed to reduced NCC in the pharyngeal and outflow regions. Here we provide a detailed map of NCC within the pharyngeal arches and outflow tract of Sp(2H)/Sp(2H) embryos and fetuses, relating this to the development of the abnormal anatomy of these structures. In the majority of Sp(2H)/Sp(2H) embryos we show that deficiency of NCC in the pharyngeal region results in a failure to stabilize, and early loss of, posterior pharyngeal arch arteries. Furthermore, marked reduction in the NCC-derived mesenchyme in the dorsal wall of the aortic sac disrupts fusion with the distal outflow tract cushions, preventing the initiation of outflow tract septation and resulting in common arterial trunk. In around 25% of Sp(2H)/Sp(2H) embryos, posterior arch arteries are stabilized and fusion occurs between the dorsal wall of the aortic sac and the outflow cushions, initiating outflow tract septation; these embryos develop double outlet right ventricle. Thus, NCC are required in the pharyngeal region both for stabilization of posterior arch arteries and initiation of outflow tract septation. Loss of NCC also disrupts the distribution of second heart field cells in the pharyngeal and outflow regions. These secondary effects of NCC deficiency likely contribute to the overall outflow phenotype, suggesting that disrupted interactions between these two cell types may underlie many common outflow defects.
斑点（2H）（Sp(2H)）是一种广为人知的神经嵴细胞（NCC）缺陷小鼠模型，会出现一系列心脏流出道畸形，包括共同动脉干、右心室双出口、室间隔缺损和咽弓动脉模式缺陷，以及其他神经嵴衍生器官系统的缺陷。这些缺陷被归因于咽和流出区域NCC数量减少。在这里，我们提供了Sp(2H)/Sp(2H)胚胎和胎儿咽弓和流出道内NCC的详细图谱，并将其与这些结构异常解剖结构的发育相关联。在大多数Sp(2H)/Sp(2H)胚胎中，我们发现咽区域NCC缺陷导致咽后弓动脉无法稳定并早期丧失。此外，主动脉囊后壁中NCC衍生的间充质显著减少，破坏了与远端流出道垫的融合，阻止了流出道分隔的启动，导致共同动脉干形成。在大约25%的Sp(2H)/Sp(2H)胚胎中，后弓动脉得以稳定，主动脉囊后壁与流出垫之间发生融合，启动流出道分隔；这些胚胎发育为右心室双出口。因此，咽区域的NCC对于后弓动脉的稳定和流出道分隔的启动都是必需的。NCC的缺失还会破坏第二心脏场细胞在咽和流出区域的分布。NCC缺陷的这些继发效应可能导致了整体流出道表型，这表明这两种细胞类型之间相互作用的破坏可能是许多常见流出道缺陷的基础。
