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The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases.

Pitx2 is a bicoid-related homeodomain transcription factor that plays a critical role in directing cardiac asymmetric morphogenesis. Ectopic Pitx2c expression in the developing myocardium correlates with double outlet right ventricle (DORV) in laterality mutants. Pitx2 loss of function experiments cause severe cardiovascular defects, such as atrial isomerism (AI), double inlet left ventricle, transposition of the great arteries (TGA), persistent truncus arteriosus (PTA), and abnormal aortic arch (AAA) remodeling. Current studies suggest that Pitx2-mediated signaling during cardiogenesis is conducted within three different cell types: the myocardium, the cardiac neural crest (CNC) cells, and the pharyngeal arch mesenchyme. Impaired Pitx2 function in discrete myocardial regions seems to lead to DORV, AI, and possibly TGA. On the other hand, impaired Pitx2 expression in the CNC leads preferentially to PTA. AAA remodeling is likely to occur owing to impaired cross-talk of the CNC cells with the pharyngeal arch mesenchyme. Thus, Pitx2 appears to be directing left-right identity to the cardiac venous components (e.g., the atria), whereas it appears to be modeling the morphologic arrangement of distinct myocardial components in the arterial pole. These data suggest that altered left-right signaling underlies the etiology of several common congenital cardiac malformations.

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