IDENTIFICATION OF GENE(S) RESPONSIBLE FOR ALAGILLE SYNDR

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We have shown earlier that mutations in the Jagged1 (JAG1) gene, which encodes a ligand for a Notch receptor, are responsible for Alagille syndrome (AGS), a developmental disorder affecting multiple organ systems including liver, heart, eye, face and vertebrae. Genes encoding other members of the Jagged and Delta families were also characterized. Since zebrafish is an excellent model for in 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 pattern. 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. Now that the mib gene has been identified, we can understand the role of the jagged and mib genes in the Notch pathway. Antisense oligonucleotides (Morpholino derivatives) are effective in bringing down the expression of genes in zebrafish, and we are pursuing the effect of blocking jagged(s) function(s) on the development of zebrafish.