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Endocardial cushion development and heart loop architecture in the trisomy 16 mouse

Murine trisomy 16 (Ts16) is a model for Down's syndrome and has close to a 100% incidence of atrioventricular septal defects (AVSDs). These have been proposed to result from abnormal development of the endocardial cushions, but the mechanisms are unknown. We aim to identify the initial defects in Ts16 hearts, both to characterise the pathogenesis of AVSDs and as a first step in the search for molecular mechanisms. In 38 litters from an Rb(11.16)2H/Rb(16.17)7Bnr × C57BL/6J cross, which was examined on days 10 and 11 of gestation, 28.4% of embryos were trisomic. Trisomic embryos were uniformly retarded compared to their normal litter mates, having on average 3.3 fewer somite pairs. All further comparisons were made between embryos of the same somitic stage. Twenty‐one trisomic and 21 normal embryos of between 15 and 43 somites were serially sectioned, and stereomorphometric methods were used to reconstruct the volumes of the endocardial cushions and to count their number of mesenchymal cells. There were fewer cells in Ts16 superior and inferior cushions. In contrast, the volumes of trisomic cushions were significantly greater than normal. Thus, cell density was markedly lower in trisomic cushions. Importantly, the volumes of the cushions in trisomic embryos were already greater than normal at the 18 somite stage, prior to the invasion of cushions by mesenchymal cells. The architecture of Ts16 heart tubes in 15–25 somite embryos was subtly abnormal. This was reflected in the angle between the axis of the atrioventricular canal and the first pharyngeal cleft, which was significantly larger in trisomic hearts and showed a different relationship to somite stage when compared to normal embryos. These observations suggest that the primary cardiac defect in Ts16 mice may be localised to the myocardium, thus influencing the shape of the heart tube, with changes in the mesenchymal population of the endocardial cushions being later events. Whether AVSDs arise from one or both of these abnormalities remains to be established. © 1996 Wiley‐Liss, Inc.