Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves.
Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves.
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DOI：
10.1093/cvr/cvv040
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发表时间：
2015-04-01
影响因子：
10.8
通讯作者：
Andrews WD
中科院分区：
文献类型：
--
作者：
Mommersteeg MT;Yeh ML;Parnavelas JG;Andrews WD
早期胚胎心脏内的间充质垫层经历了复杂的改造，在以后的生命中形成了膜性室间隔以及房室瓣和半月瓣。这一过程的中断是最常见的先天性心脏缺陷的基础。在这里，我们确定了Sit-Robo信号在小鼠膜性室间隔和心脏瓣膜发育中的一个新的作用。Robo1和Robo2受体及其配体Slit2和SLIT3在所有心脏垫/瓣膜内或其附近均有表达。Robo1缺失或同时缺失Robo1和Robo2会导致出生时膜性室间隔缺陷，这种缺陷也在SLIT3中发现，但在Slit2突变体中不存在。此外，Robo1；Robo2双突变体显示未成熟的半月瓣和房室瓣增厚，以及高度穿透的二尖瓣。SLIT2突变型表现为半月型，而SLIT3突变型表现为房室瓣增厚。在Robo1；Robo2双突变体中，E12.5处已经观察到二尖瓣的主动脉垫。在Robo1突变体中，Notch及其下游的嘿和Hes基因的表达下调，这表明缺乏Robo的小鼠的Notch信号减少可能是导致缺陷的原因。荧光素酶检测证实了Robo对Notch信号的调控。Robo或Sit基因突变的心脏缺陷范围从膜性室间隔缺陷到二尖瓣主动脉瓣。这些配体和受体在特定的心脏垫衍生物的形成过程中具有独特的功能，Sit-Robo信号通路可能通过调节Notch信号来加强其作用，使这些突变体成为研究心脏瓣膜形成的有价值的新模型。
The mesenchymal cushions lining the early embryonic heart undergo complex remodelling to form the membranous ventricular septum as well as the atrioventricular and semilunar valves in later life. Disruption of this process underlies the most common congenital heart defects. Here, we identified a novel role for Slit-Robo signalling in the development of the murine membranous ventricular septum and cardiac valves. Expression of Robo1 and Robo2 receptors and their ligands, Slit2 and Slit3, was present in or adjacent to all cardiac cushions/valves. Loss of Robo1 or both Robo1 and Robo2 resulted in membranous ventricular septum defects at birth, a defect also found in Slit3, but not in Slit2 mutants. Additionally, Robo1;Robo2 double mutants showed thickened immature semilunar and atrioventricular valves as well as highly penetrant bicuspid aortic valves. Slit2 mutants recapitulated the semilunar phenotype, whereas Slit3 mutants displayed thickened atrioventricular valves. Bicuspid aortic cushions were already observed at E12.5 in the Robo1;Robo2 double mutants. Expression of Notch- and downstream Hey and Hes genes was down-regulated in Robo1 mutants, suggesting that reduced Notch signalling in mice lacking Robo might underlie the defects. Luciferase assays confirmed regulation of Notch signalling by Robo. Cardiac defects in mutants for Robo or Slit range from membranous ventricular septum defects to bicuspid aortic valves. These ligands and receptors have unique functions during development of specific cardiac cushion derivatives, and the Slit-Robo signalling pathway likely enforces its role by regulating Notch signalling, making these mutants a valuable new model to study cardiac valve formation.
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影响因子：
64.5
作者：
Brose, K;Bland, KS;Kidd, T
通讯作者：
Kidd, T
影响因子：
3.7
作者：
Rochais F;Dandonneau M;Mesbah K;Jarry T;Mattei MG;Kelly RG
通讯作者：
Kelly RG
影响因子：
4.6
作者：
Fish, Jason E.;Wythe, Joshua D.;Woo, Stephanie
通讯作者：
Woo, Stephanie
DOI：
10.1016/j.jtcvs.2007.02.041
发表时间：
2007-08-01
影响因子：
6
作者：
McKellar, Stephen H.;Tester, David J.;Sundt, Thoralf M., III
通讯作者：
Sundt, Thoralf M., III
影响因子：
15.9
作者：
Jain, Rajan;Engleka, Kurt A.;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.