Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shanxi 710061, China.
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cardiovasc Res. 2020 Jul 1;116(8):1473-1486. doi: 10.1093/cvr/cvz249.
Sinus venous valve (SVV) and sinoatrial node (SAN) develop together at the sinoatrial junction during embryogenesis. SVV ensures unidirectional cardiac input and SAN generates sinus rhythmic contraction, respectively; both functions are essential for embryonic survival. We aim to reveal the potential role of endocardial NOTCH signalling in SVV and SAN formation.
We specifically deleted Notch1 in the endocardium using an Nfatc1Cre line. This deletion resulted in underdeveloped SVV and SAN, associated with reduced expression of T-box transcription factors, Tbx5 andTbx18, which are essential for the formation of SVV and SAN. The deletion also led to decreased expression of Wnt2 in myocardium of SVV and SAN. WNT2 treatment was able to rescue the growth defect of SVV and SAN resulted from the Notch1 deletion in whole embryo cultures. Furthermore, the Notch1 deletion reduced the expression of Nrg1 in the SVV myocardium and supplement of NRG1 restored the growth of SVV in cultured Notch1 knockout embryos.
Our findings support that endocardial NOTCH1 controls the development of SVV and SAN by coordinating myocardial WNT and NRG1 signalling functions.
窦房静脉瓣 (SVV) 和窦房结 (SAN) 在胚胎发生过程中在窦房结处一起发育。SVV 确保单向心脏输入，而 SAN 分别产生窦性节律性收缩，这两个功能对胚胎存活都是必不可少的。我们旨在揭示心内膜 NOTCH 信号在 SVV 和 SAN 形成中的潜在作用。
我们使用 Nfatc1Cre 线特异性地在心内膜中缺失 Notch1。这种缺失导致 SVV 和 SAN 发育不良，与 T 盒转录因子 Tbx5 和 Tbx18 的表达减少有关，这些因子对于 SVV 和 SAN 的形成是必不可少的。缺失还导致 SVV 和 SAN 心肌中 Wnt2 的表达减少。WNT2 处理能够挽救 Notch1 缺失导致的 SVV 和 SAN 生长缺陷在整个胚胎培养物中。此外，Notch1 缺失减少了 SVV 心肌中 Nrg1 的表达，而 NRG1 的补充恢复了 Notch1 敲除胚胎中 SVV 的生长。
我们的研究结果表明，心内膜 NOTCH1 通过协调心肌 WNT 和 NRG1 信号功能来控制 SVV 和 SAN 的发育。
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