Pitx2 and Cardiac Development: A Molecular Link between Left/Right Signaling and Congenital Heart Disease

Abstract

Cardiac development is a complex and dynamic process(Fishman and Chien 1997). The heart develops from a bilateral set of promyocardial cells located at either side ofthe embryonic midline. The left and right sides of the cardiac crescent eventually fuse along the midline of the embryo, leading to a straight cardiac tube. This straight tubecomprises an outer myocardial layer lined on the innerside by an endocardial layer (Manasek 1968). Soon after,the heart tube bends rightward, displaying the first morphological sign of left/right asymmetry in the developingembryo (Stalsberg 1969). With further development, atrialand ventricular chamber-specific gene expression is activated in discrete regions of the looped heart, delineatingthe embryonic heart (Christoffels et al. 2000). At thisstage, five different regions can be observed in the developing heart: inflow tract, atrial myocardium, atrioventricular canal, ventricular myocardium, and outflow tract.These regions display different gene expression profilesand have different functional properties (Franco et al.1998, 2000; Moorman et al. 1998). In mammals, each ofthese regions divides into two components to generate adouble circulatory system. Interestingly, myocardial differentiation continues at the inflow tract of the heart, allowing the pulmonary and caval vessels to acquire distinctmyocardial components. We have recently documented inmice that the gene expression profiles of the caval and pulmonary vessels diverge from each other, as well as fromthe surrounding atrial myocardium, supporting the notionthat multiple myocardial domains are present in the developing and fully formed inflow tract (Franco et al. 2000).In essence, the developing heart exhibits extensive transcriptional diversity, suggesting that at least seven different domains can be delineate...