DEVELOPMENTAL EXPRESSION OF JAGGED1 IN THE MAMMALIAN HEART: IMPLICATIONS FOR CARDIAC DISEASE IN ALAGILLE SYNDROME

Abstract

24 Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the liver, heart, eye, skeleton and kidney. Congenital heart defects, the majority of which are right-sided, contribute significantly to mortality in AGS patients. Mutations in Jagged1, a conserved gene in the Notch intercellular signaling pathway, have been found to cause AGS. In order to understand the role of Jagged1 in normal heart development and in the heart defects seen in AGS, we have studied the expression pattern of Jagged1 in the developing mammalian heart. Jagged1 expression was assayed by whole mount and section in situ hybridizations on mouse and human embryos. Whole mount in situ hybridizations of mouse embryos at 8.0 and 8.5 days post coitum (dpc), corresponding to 3 weeks of human gestation, reveal Jagged1 expression in the first pharyngeal arch. Jagged1 is expressed in the human heart at 8 weeks of gestation transmurally in the atria and in the endocardium of the ventricles. Expression is also detected in the epicardium, which is derived from liver primordium. In order to identify vascular structures in the mouse embryo at 10.5 dpc, in situ hybridization was performed with a probe for PECAM, an endothelial cell marker. Combined studies with probes for Jagged1 and PECAM show overlapping patterns of expression in the branchial arch arteries and descending aorta, confirming Jagged1 expression in these vascular structures. In situ hybridization of mouse embryos at 12.5 dpc shows Jagged1 expression in the endothelial cells of the endocardial cushions which will undergo mesenchymal transformation to form value tissue. Expression is particularly accentuated in the right-sided outflow tract, ductus arteriosus, pulmonary arteries and lung mesoderm. We conclude that Jagged1 is expressed in the developing mammalian heart in multiple vascular structures and in the developing valves. This pattern of expression provides evidence that Jagged1 has a direct role in cardiac development and that the sites of expression correlate with the congenital heart defects seen in AGS.