Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome
Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome
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DOI：
10.1242/dev.084871
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发表时间：
2012-12-01
期刊：
影响因子：
4.6
通讯作者：
Iruela-Arispe, M. Luisa
中科院分区：
文献类型：
--
作者：
Hofmann, Jennifer J.;Briot, Anais;Iruela-Arispe, M. Luisa
Notch信号通路对心血管系统的发育和稳态起着重要的作用。不足为奇的是，Notch受体和配体的突变与影响心脏和脉管系统的各种遗传性疾病有关。特别是，编码人类Notch配体jagged 1的基因突变导致一种称为Alagille综合征的多系统常染色体显性疾病，其中包括法洛四联症，这是一种更严重的心脏疾病。Jagged 1在发育中的胚胎中表达，尤其是在内皮细胞中。在这里，我们证明了内皮特异性的Jag1缺失会导致胚胎和成年小鼠的心血管缺陷，这让人联想到Alagille综合征。突变小鼠表现为右心室肥厚、覆盖主动脉、室间隔缺损、冠状动脉异常和瓣膜缺损。对妊娠中期胚胎的检查显示，Jag1的缺失与Notch1的缺失类似，会破坏心内膜缓冲形成过程中内皮细胞向间充质细胞的转变。此外，成年突变小鼠表现出与异常基质重塑和诱导骨形态发生相关的心脏瓣膜钙化。这项工作表明，内皮细胞负责在Alagille综合征中显示的广泛的心脏表型，并且它证明了Jag1在瓣膜形态发生中的关键作用。
The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.