Waller B R, McQuinn T, Phelps A L, Markwald R R, Lo C W, Thompson R P, Wessels A
Department of Cell Biology & Anatomy, Cardiovascular Developmental Biology Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Anat Rec. 2000 Nov 1;260(3):279-93. doi: 10.1002/1097-0185(20001101)260:3<279::AID-AR65>3.0.CO;2-2.
The trisomy 16 (Ts16) mouse is generally considered a model for human Down's syndrome (trisomy 21). However, many of the cardiac defects in the Ts16 mouse do not reflect the heart malformations seen in patients suffering from this chromosomal disorder. In this study we describe the conotruncal malformations in mice with trisomy 16. The development of the outflow tract was immunohistochemically studied in serially sectioned hearts from 34 normal and 26 Ts16 mouse embryos ranging from 8.5 to 14.5 embryonic days. Conotruncal malformations observed in the Ts 16 embryos included double outlet right ventricle, persistent truncus arteriosus, Tetralogy of Fallot, and right-sided aortic arch. This spectrum of malformations is remarkably similar to that seen in humans suffering from DiGeorge syndrome (DGS). As perturbation of neural crest development has been proposed in the pathogenesis of DGS we specifically focussed on the fate of neural crest derived cells during outflow tract development of the Ts16 mouse using an antibody that enabled us to trace these cells during development. Severe perturbation of the neural crest-derived cell population was observed in each trisomic specimen. The abnormalities pertained to: 1) the size of the columns of neural crest-derived cells (or prongs); 2) the spatial orientation of these prongs within the mesenchymal tissues of the outflow tract; and 3) the location in which the neural crest cells interact with the myocardium. The latter abnormality appeared to be responsible for ectopic myocardialization found in trisomic embryos. Our observations strongly suggest that abnormal neural crest cell behavior is involved in the pathogenesis of the conotruncal malformations in the Ts16 mouse.
16三体（Ts16）小鼠通常被认为是人类唐氏综合征（21三体）的模型。然而，Ts16小鼠的许多心脏缺陷并不能反映出患有这种染色体疾病的患者所出现的心脏畸形。在本研究中，我们描述了16三体小鼠的圆锥干畸形。对34只正常和26只Ts16小鼠胚胎（胚胎日龄为8.5至14.5天）的连续切片心脏进行免疫组织化学研究，以观察流出道的发育情况。在Ts16胚胎中观察到的圆锥干畸形包括右心室双出口、永存动脉干、法洛四联症和右侧主动脉弓。这种畸形谱与患有DiGeorge综合征（DGS）的人类患者所出现的畸形谱非常相似。由于有人提出神经嵴发育的扰动参与了DGS的发病机制，我们使用一种抗体，专门关注Ts16小鼠流出道发育过程中神经嵴衍生细胞的命运，该抗体使我们能够在发育过程中追踪这些细胞。在每个三体标本中都观察到了神经嵴衍生细胞群体的严重扰动。这些异常包括：1）神经嵴衍生细胞柱（或叉）的大小；2）这些叉在流出道间充质组织内空间方向；3）神经嵴细胞与心肌相互作用的位置。后一种异常似乎是三体胚胎中异位心肌化的原因。我们的观察结果强烈表明，异常的神经嵴细胞行为参与了Ts16小鼠圆锥干畸形的发病机制。
