Endocardial Cushion Formation in Zebrafish

Cardiac valves form at three sites along the anteroposterior (AP) axis of the developing heart: the outflow tract,atrioventricular (AV) boundary, and sinus venosus. Theirfunction is to ensure unidirectional blood flow throughthe heart. Cardiac valves derive from endocardial cellsthat first form endocardial cushions, which are later remodeled into valves and septae. Prior to valve formation,the cushions themselves may be critical in controlling intracardiac flow; therefore, derangement of endocardialcushion formation can lead to lethality from early embryonic stages. In mammals, disrupted endocardial cushionformation leads to various heart defects, including particular types of atrial septal defects (ASDs), ventricular septal defects (VSDs), and, in the most severe form, AVcanal defects (aka AV septal or endocardial cushion defects). AV canal defects account for 5% of cases of human congenital heart disease (CHD) (i.e., 1600 cases inthe U.S. per year), making it the fourth most commoncongenital heart malformation, and the fifth most common cause of death due to congenital heart disease (Emmanouilides et al. 1998). AV canal defects are also common in Down syndrome, where 16% of patients exhibitcomplete AV canal defects with all four chambers of theheart in open communication. AV canal defects are alsocommon in isomerism syndromes (especially right isomerism) and in DiGeorge and Ellis-van Creveld syndromes (both of which are associated with incompleteAV canal defects). Septal defects (VSDs and ASDs),which are much more common than AV canal defects,can result from minor defects in endocardial cushion formation...