Hedgehog signaling during cardiovascular patterning in the mouse

描述（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。流出道发育缺陷导致严重的先天性心脏缺陷，如持续性动脉干和双出口右心室。同样，房室（A-V）缓冲有助于二尖瓣和三尖瓣以及成人心脏间隔的形成。A-V缓冲发育异常可导致严重的先天性心脏缺陷，如A-V管或三尖瓣和二尖瓣闭锁。因此，了解流出道的形成和A-V缓冲的发展对了解许多先天性心脏缺陷的发展至关重要。经典研究表明，心脏神经嵴细胞（CNCC）在分离单一流出道进入主动脉和肺动脉的过程中是必需的。最近的研究为心脏流出道心肌的发育提供了新的见解。这些研究表明心脏前体细胞存在于流出道和右心室。我们的初步数据表明，Shh信号通路对这些“前心野”（AHF）细胞以及流出道形成和分离过程中的迁移性CNCC至关重要。此外，Shh似乎是A-V缓冲层形成和瓣膜发育所必需的。Shh信号的缺失导致单个流出道（肺动脉闭锁）和单个a - v阀。我们认为，在Shh突变体中发现的心脏缺陷是由于流出道发育过程中CNCC和AHF的异常发育以及瓣膜形成过程中心内膜垫的异常形成所致。我们建议使用Cre/LoxP方法检查AHF和CNCC在流出道协调发展中对hedgehog信号的细胞自主需求。同样，我们将在小鼠中使用遗传操作测试A-V阀形成过程中hedgehog信号的细胞自主需求。

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.