IDENTIFICATION OF THE GENE(S) RESPONSIBLE FOR ALAGILLESY

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Mutations in the Jagged1 (JAG1) gene, which encodes a ligand for a Notch receptor, are responsible for Alagille syndrome (AGS). AGS is a developmental disorder affecting multiple organ systems including liver, heart, eye, face and vertebrae. Human diseases and mouse phenotypes associated mutations in many other members of the Notch pathway have been described. Since zebrafish is an excellent model for vertebrate development, we have isolated and characterized Jagged homologous genes from zebrafish in order to explore their role in developmental diseases like Alagille syndrome. Three jaggeds termed Jagged 1, 2 and 3 were characterized, along with their chromosomal location and expression. The effect of their (ectopic) expression during zebrafish embryonic development and in mib mutants with a neurogenic phenotype has been studied. Ectopic expression of jagged RNAs leads to a reduction of neurons in both wild and mib mutant embryos. Positional cloning revealed that mib is a novel gene in the Notch pathway, a RING E3 ubiquitin ligase which plays a key role in ubiquitylation. Antisense oligonucleotides (Morpholino derivatives) generated for Jaggeds 1, 2 and 3 are being used to explore their role in liver development, and to a better understanding of the Alagille syndrome.