EXPRESSION PATTERN OF JAGGEDI DURING MOUSE AND HUMAN DEVELOPMENT: IMPLICATIONS FOR ALAGILLE SYNDROME

Abstract

174 Background/Aims: Alagille syndrome is an autosomal dominant disorder characterized by developmental abnormalities of the liver, heart, face, eye, skeleton and kidney. Recently, mutations in humanJaggedl, an evolutionarily conserved gene in the Notch intercellular signaling pathway, have been found to cause Alagille syndrome. In order to understand the role of Jaggedl in normal development and in the causation of anomalies present in Alagille syndrome, we have undertaken a series of experiments to define the temporal and spatial expression ofJaggedl in the developing human and mouse. Methods:Jaggedl expression was assayed by reverse transcriptase-polymerase chain reaction (RT-PCR). Expression was also assayed by whole mount and section in situ hybridizations on mouse and human embryos. Antisense and sense riboprobes were generated corresponding to conserved regions of the human Jaggedl gene. Results: By RT-PCR, Jaggedl is expressed in mouse embryos at stages 9.5 days post coitum (dpc) through 12.5 dpc. These stages correspond to approximately 3-8 weeks in human gestation.Jaggedl is also expressed in adult mouse liver, heart, lung, kidney and pancreas. Whole mount in situ hybridization reveals strong expression of Jaggedl in the 8.5 dpc mouse embryo in the first branchial arch. At 9.5 dpc, expression is detected in all branchial arches, heart and developing kidney. At 10.5 dpc, expression decreases in the branchial arches, but increases in the heart, eye, limb buds and intersomitic spaces. In situ hybridization of sagittal sections of ahuman 56 day embryo shows widespread expression. Gene expression is detected throughout lung and kidney, in the liver, brain, intestine and intersomitic spaces. In the heart, expression is stronger in the atria than in the ventricles. Jaggedl is also expressed in the aorta and the coronary arteries. Expression patterns in mouse embryo sections at 10.5 dpc are very similar to those observed in the 8 week human embryo. No signal is detected on slides hybridized with sense (control) probes. Conclusions:Jaggedl is widely expressed during mammalian embryonic development. In many tissues, such as liver, heart, kidney and eye, the expression corresponds to the organs affected in classic Alagille syndrome. Less common clinical phenotypes, such as intestinal atresia and shortened distal phalanges, may correlate with Jaggedl expression observed in intestine and limb buds.