Recovery from arterial growth delay reduces penetrance of cardiovascular defects in mice deleted for the DiGeorge syndrome region
Recovery from arterial growth delay reduces penetrance of cardiovascular defects in mice deleted for the DiGeorge syndrome region
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DOI：
10.1093/hmg/10.9.997
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发表时间：
2001-04-15
影响因子：
3.5
通讯作者：
Baldini, A
中科院分区：
文献类型：
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作者：
Lindsay, EA;Baldini, A
染色体22q11.2杂合缺失导致最常见的缺失综合征，包括DiGeorge综合征表型。使用该缺失的小鼠模型(命名为Df1)，我们发现发生在杂合缺失小鼠(Df1/+)中的主动脉弓图案缺陷与早期胚胎发育过程中第四咽弓动脉(PaaS)的血管平滑肌分化障碍有关。利用分子标记技术对神经峰、内皮细胞和血管平滑肌进行分析，我们发现在Df1/+胚胎中，心脏神经峰向第4弓的迁移和第4弓的初始形成是明显正常的，但受影响的血管生长受损，不能获得血管平滑肌，与人类一样，并非所有缺失的小鼠在出生时都存在心血管缺陷。然而，我们意外地发现，在胚胎发育的早期，所有Df1/+胚胎都有异常小的第4 PaAS。许多胚胎后来克服了这一早期缺陷，与血管平滑肌分化的出现相一致，并正常发育，出生时患有主动脉弓型缺陷的胚胎可能代表了一个更严重的组，无法获得足够的第四PAA生长来正常重建PAA系统。我们的数据表明，DF1/+胚胎能够克服局部动脉生长障碍，从而减少出生缺陷的外显率。
Chromosome 22q11.2 heterozygous deletions cause the most common deletion syndrome, including the DiGeorge syndrome phenotype, Using a mouse model of this deletion (named Df1) we show that the aortic arch patterning defects that occur in heterozygously deleted mice (Df1/+) are associated with a differentiation impairment of vascular smooth muscle in the 4th pharyngeal arch arteries (PAAs) during early embryogenesis. Using molecular markers TOT neural crest, endothelial cells ana vascular smooth muscle, we show that cardiac neural crest migration into the 4th arch and initial formation of the 4th PAAs are apparently normal in Df1/+ embryos, but affected vessels are growth-impaired and do not acquire vascular smooth muscle, As in humans, not all deleted mice present with cardiovascular defects at birth, However, we found, unexpectedly, that all Df1/+ embryos have abnormally small 4th PAAs during early embryogenesis. Many embryos later overcome this early defect, coincident with the appearance of vascular smooth muscle differentiation, and develop normally, Embryos born with aortic arch patterning defects probably represent a more severely affected group that fails to attain sufficient 4th PAA growth for normal remodelling of the PAA system. Our data indicate that Df1/+ embryos are able to overcome a localized arterial growth impairment and thereby reduce the penetrance of birth defects.