Hedgehog signaling during cardiovascular patterning in the mouse

描述（由申请人提供）：胚胎心脏的流出道有助于主动脉和肺动脉的形成。流出道发育的缺陷导致严重的先天性心脏病，如永存动脉干和右心室双出口。类似地，房室（A-V）垫有助于二尖瓣和三尖瓣以及成人心脏隔膜的形成。房室垫发育异常可导致严重的先天性心脏病，如房室管或三尖瓣和二尖瓣闭锁。因此，了解流出道的形成和房室垫的发展对于了解许多先天性心脏病的发展至关重要。经典的研究已经证明了心脏神经嵴细胞（CNCC）在单一流出道进入主动脉和肺动脉的分隔中的需要。最近的研究为心脏流出道心肌的发育提供了新的见解。这些研究证明了心脏前体细胞的存在，这些细胞被添加到流出道和右心室。我们的初步数据表明，Shh信号通路是至关重要的，这些“心前区”（AHF）细胞以及迁移CNCC在流出道形成和分隔。此外，Shh似乎是房室垫形成所需的，因此也是瓣膜发育所需的。Shh信号的丢失导致单个流出道（肺动脉闭锁）和单个A-V瓣膜。我们建议，心脏缺陷中看到的Shh突变体是由于异常发展的CNCC和AHF在流出道的发展，以及异常内膜垫形成瓣膜形成过程中。我们建议检查AHF和CNCC中的流出道的协调发展中使用的Cre/LoxP的方法刺猬信号的细胞自主的要求。类似地，我们将在小鼠中使用遗传操作测试A-V瓣膜形成期间刺猬信号传导的细胞自主要求。

DESCRIPTION (provided by applicant): The outflow tract of the embryonic heart contributes to the formation of the aortic and pulmonary artery. Defects in outflow tract development result in severe congenital heart defects such as persistent truncus arteriosus and double outlet right ventricle. Similarly, atrio-ventricular (A-V) cushions contribute to the formation of the mitral and tricuspid valves as well as to the septa of the adult heart. Abnormalities in A-V cushion development can result in severe congenital heart defects such as A-V canal or tricuspid and mitral valve atresias. Understanding how the outflow tract forms and the A-V cushions develop is therefore critical to understanding the development of many congenital heart defects. Classic studies have demonstrated the requirement of cardiac neural crest cells (CNCC) in the septation of the single outflow tract into the aortic and pulmonary arteries. More recent studies have provided new insight into the development of the myocardium of the outflow tract of the heart. These studies demonstrate the existence of heart precursor cells that are added to the outflow tract and right ventricle. Our preliminary data suggests that the Shh signaling pathway is critical for these "anterior heart field" (AHF) cells as well as for migratory CNCC during outflow tract formation and septation. In addition, Shh appears to be required for A-V cushion formation and therefore valve development. Loss of the Shh signal results in a single outflow tract (pulmonary artery atresia) and a single A-V valve. We propose that the cardiac defects seen in Shh mutants are due to abnormal development of both CNCC and the AHF during outflow tract development as well as abnormal endocardial cushion formation during valve formation. We propose examining the cell autonomous requirement for hedgehog signaling within AHF and CNCC in the coordinated development of the outflow tract using a Cre/LoxP approach. Similarly we will test the cell autonomous requirement of hedgehog signaling during A-V valve formation using genetic manipulations in the mouse.