Conotruncal anomalies in the trisomy 16 mouse: an immunohistochemical analysis with emphasis on the involvement of the neural crest

The trisomy 16 (Ts16) mouse is generally considered a model for human Down' s syndrome (trisomy 21). However, many of the cardiac defects in the Ts16 m ouse do not reflect the heart malformations seen in patients suffering from this chromosomal disorder. In this study we describe the conotruncal malfo rmations in mice with trisomy 16. The development of the outflow tract was immunohistochemically studied in serially sectioned hearts from 34 normal a nd 26 Ts16 mouse embryos ranging from 8.5 to 14.5 embryonic days. Conotrunc al malformations observed in the Ts 16 embryos included double outlet right ventricle, persistent truncus arteriosus, Tetralogy of Fallot, and right-s ided aortic arch. This spectrum of malformations is remarkably similar to t hat seen in humans suffering from DiGeorge syndrome (DGS). As perturbation of neural crest development has been proposed in the pathogenesis of DGS we specifically focussed on the fate of neural crest derived cells during out flow tract development of the Ts16 mouse using an antibody that enabled us to trace these cells during development. Severe perturbation of the neural crest-derived cell population was observed in each trisomic specimen. The a bnormalities pertained to: 1) the size of the columns of neural crest-deriv ed cells (or prongs); 2) the spatial orientation of these prongs within the mesenchymal tissues of the outflow tract; and 3) the location in which the neural crest cells interact with the myocardium. The latter abnormality ap peared to be responsible for ectopic myocardialization found in trisomic em bryos. Our observations strongly suggest that abnormal neural crest cell be havior is involved in the pathogenesis of the conotruncal malformations in the Ts16 mouse. Anat Rec 260:279-293, 2000. (C) 2000 Wiley-Liss, Inc.