International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G21 Expression of Jagged1 During Mammalian Development and Its Relationship to Human Disease

K. M. Loomes1, N..B. Spinner2, D. A. Piccoli1, H. S. Baldwin3 and R. J. Oakey2. Divisions of Gastroenterology1, Human Genetics2 and Cardiology3, Children's Hospital of Phila., Univ. of PA School of Medicine, Phila., PA

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the heart, liver, 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 development and in the defects seen in AGS, we have studied the expression pattern of Jagged1 in the developing mouse and human. These data are consistent with an important role for Jagged1 and Notch signaling in early mammalian cardiac development. A histological analysis of a series of mouse and human embryos hybridized with Jagged1, has revealed a strong correlation between affected structures in AGS patients and sites of expression.

Jagged1 expression was assayed by whole mount and section in situ hybridizations on mouse and human embryos. Jagged1 mRNA is detected early in mouse development (from ~7.5dpc) in structures destined to become part of the developing cardiovascular system such as the pharyngeal arches. Jagged1 mRNA is detected in the murine heart valves as well as the great vessels in a pattern similar to that seen in the developing human. An abundance of Jagged1 expression is found in the outflow tracts, the pulmonary artery, ductus arteriosus and descending aorta. Interestingly, expression is not restricted to endothelial cells but is also clearly evident in the peri-endothelial population of cells. Given the recent evidence to suggest an intimate and critical relationship between endothelial and smooth muscle differentiation during vascular development these observations are particularly intriguing.

Because the majority of patients with AGS have narrowing at some level in the pulmonary vasculature, we examined Jagged1 expression in the developing human and mouse lung. Jagged1 expression is detected in the human 56d embryonic lung with rings of expression around the airways and blood vessels. By contrast in the mouse, very little expression is detected in the corresponding 12-13dpc lung except in the proximal pulmonary vasculature. In 18.5dpc and newborn mouse lungs, Jagged1 expression is detected in airways and large vessels but spares the small capillaries. Thus the timing of expression of Jagged1 between these two species is different, but distinctive rings of Jagged1 expression around the developing airways and blood vessels in both species point to a role for Jagged1 and the Notch signaling pathway in lung development.

Jagged1 is also detected in other organs affected in AGS. For example, Jagged1 is expressed throughout the parenchyma of the kidney in the vertebral column of a human 56d embryo, in the developing mouse limb bud and the developing mouse eye. The liver, a major site of disease in AGS patients, has a highly restricted and well defined pattern of Jagged1 expression. These sites of expression in the liver correlate with bile duct paucity, one of the major phenotypes in addition to heart disease in affected children.


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