Mohun group
A mouse model for Down Syndrome cardiac defects
(Collaborators: Victor Tybulewicz, NIMR; Elizabeth Fisher, Institute of Neurology, UCL; Mark Lythgoe, CABI, UCL)
(Funding: Wellcome Trust)
Trisomy of human chromosome 21 (Hsa21) occurs in ~1 in 750 live births, and the resulting gene dosage imbalance gives rise to Down Syndrome (DS). Around 45% of people with DS have a congenital heart defect. A mouse model of trisomy 21 has recently been created by Victor Tybulewicz and Elizabeth Fisher to study the genes responsible for the different aspects of Down Syndrome. The Tc1 mouse strain carries a freely segregating copy of virtually all of Hsa21 and exhibits many aspects of phenotype similar to human Down Syndrome. As part of this Wellcome Foundation-funded project, we are investigating the spectrum of heart malformations that occur in the Tc1 mouse to assess its utility as a model of the cardiac malformations prevalent in Down Syndrome.
3D modelling techniques including optical projection tomography (OPT) and high resolution episcopic microscopy (HREM) are being used in conjunction with traditional histology to give a clear and thorough analysis of the heart phenotypes seen in the Tc1 mouse. The incidence of heart defects observed in Tc1 embryos varies depending on the genetic background.; embryos generated with C57BL/6 males have a higher occurrence of heart defects (71%) than those generated with F1 C57BL/6:129S8 males (39%).
Figure 6
Tc1 embryos exhibit both perimembranous VSD, A and C, and inlet VSD, B. Either alone, A, or in combination, B and C are the same sample.
The majority of heart defects exhibited by Tc1 embryos are ventricular septal defects, affecting the perimembranous and inlet regions of the ventricular septum. Double-outlet right ventricle, overriding aorta, persistent truncus arteriosus and endocardial cushion defects are also observed. Like the atrioventricular defects seen in DS, these suggest that the primary lesion resulting from presence of Hsa21 in the Tc1 mouse affects an early step in cardiogenesis, resulting in malformations affecting the AV junction. The initial goal is to characterise these through analysis of cardiac morphology and examination of candidate gene expression patterns.
Figure 7
Tc1 embryos exhibit endocardial cushion defects including cleft of the mitral valve (A), failure of the endocardial cushions to fuse (B).Arrowhead in B marks a VSD.
The Tc1 mouse model represents an important tool to study the manner in which of gene dosage anomalies on the production of heart defects and another goal of this project is to use mice produced either by further chromosome engineering or by crossing Tc1 with individual gene knockouts to identify which genes on Hsa21 are responsible for each aspect of the DS-like phenotype. Our studies aim to identify those genes that cause malformations in AV junction formation when present in trisomic gene dosage.
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