Sequential Notch activation regulates ventricular chamber development.
Sequential Notch activation regulates ventricular chamber development.
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DOI：
10.1038/ncb3280
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发表时间：
2016-01
影响因子：
21.3
通讯作者：
de la Pompa JL
中科院分区：
文献类型：
--
作者：
D'Amato G;Luxán G;del Monte-Nieto G;Martínez-Poveda B;Torroja C;Walter W;Bochter MS;Benedito R;Cole S;Martinez F;Hadjantonakis AK;Uemura A;Jiménez-Borreguero LJ;de la Pompa JL
心室对于生命中每一次心跳的节律性收缩和放松是必不可少的。先天性心室形成异常导致严重的人类心脏缺陷。心肌纤维的早期小梁网如何形成并随后发展成成熟的腔室尚不清楚。我们发现Notch信号首先连接心室心内膜和心肌以维持小梁，然后通过由糖基转移酶躁狂条纹（MFng）决定的配体信号的时间序列，协调心室模式和压实与冠状血管的发育，以产生成熟的心室。早期心内膜表达MFng可促进Dll4-Notch1信号传导，从而诱导发育中的心室小梁。心室成熟和压实需要心内膜中MFng和Dll4的下调，这使得心肌Jag1和Jag2向该组织中的Notch1发出信号。这种信号平衡的扰动严重破坏了心腔的形成。我们的研究结果为心肌病的发病机制开辟了一条新的研究途径。
Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4–Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies.