Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Cardiovasc Res. 2013 Aug 1;99(3):452-60. doi: 10.1093/cvr/cvt132. Epub 2013 May 30.
Anomalies of the arterial valves, principally bicuspid aortic valve (BAV), are the most common congenital anomalies. The cellular mechanisms that underlie arterial valve development are poorly understood. While it is known that the valve leaflets derive from the outflow cushions, which are populated by cells derived from the endothelium and neural crest cells (NCCs), the mechanism by which these cushions are sculpted to form the leaflets of the arterial valves remains unresolved. We set out to investigate how NCCs participate in arterial valve formation, reasoning that disrupting NCC within the developing outflow cushions would result in arterial valve anomalies, in the process elucidating the normal mechanism of arterial valve leaflet formation.
By disrupting Rho kinase signalling specifically in NCC using transgenic mice and primary cultures, we show that NCC condensation within the cardiac jelly is required for correct positioning of the outflow cushions. Moreover, we show that this process is essential for normal patterning of the arterial valve leaflets with disruption leading to a spectrum of valve leaflet patterning anomalies, abnormal positioning of the orifices of the coronary arteries, and abnormalities of the arterial wall.
NCCs are required at earlier stages of arterial valve development than previously recognized, playing essential roles in positioning the cushions, and patterning the valve leaflets. Abnormalities in the process of NCC condensation at early stages of outflow cushion formation may provide a common mechanism underlying BAV, and also explain the link with arterial wall anomalies and outflow malalignment defects.
动脉瓣异常，主要是二叶式主动脉瓣（BAV），是最常见的先天性异常。动脉瓣发育的细胞机制尚不清楚。虽然已知瓣叶起源于流出垫，流出垫由来源于内皮和神经嵴细胞（NCC）的细胞组成，但这些垫如何被塑造以形成动脉瓣的瓣叶的机制仍未解决。我们着手研究 NCC 如何参与动脉瓣形成，认为在发育中的流出垫中破坏 NCC 会导致动脉瓣异常，在此过程中阐明了动脉瓣瓣叶形成的正常机制。
通过使用转基因小鼠和原代培养物特异性破坏 Rho 激酶信号转导，我们表明 NCC 在心脏果冻中的凝聚对于流出垫的正确定位是必需的。此外，我们表明，这个过程对于动脉瓣瓣叶的正常模式形成是必不可少的，破坏会导致瓣叶模式形成异常、冠状动脉口的异常定位以及动脉壁的异常。
NCC 在动脉瓣发育的早期阶段比以前认为的更为重要，在定位垫和塑造瓣叶方面发挥着重要作用。在流出垫形成的早期阶段 NCC 凝聚过程中的异常可能为 BAV 提供了一个共同的机制，并解释了与动脉壁异常和流出错位缺陷的联系。
