Jagged1 (JAG1) gene encodes a ligand for a Notch receptor, and mutations in the JAG1 are responsible for Alagille syndrome (AGS). Mutations in many other members of the Notch pathway have also been found to be associated with human diseases and mouse phenotypes. Zebrafish is an excellent model for vertebrate development, and therefore we have initiated efforts to explore the role of jagged genes in zebrafish development and in developmental diseases like Alagille syndrome. As a part of this effort, we have isolated and characterized Jagged homologous genes from zebrafish. Three genes termed jagged 1, 2 and 3 were isolated and characterized, along with their chromosomal location and expression. Ectopic expression of jagged RNAs leads to a reduction of neurons in "mind bomb" (mib) mutant embryos in which reduced lateral inhibition permits too many neural progenitors to differentiate into neurons. Positional cloning revealed that the mib is a novel gene in the Notch pathway, which encodes a RING Ubiquitin ligase that is essential for efficient activation of Notch by Delta. Antisense oligonucleotides (Morpholino derivatives) generated for Jaggeds 1, 2 and 3 are being used to explore their role in liver development. Combinations of jagged and notch gene knockdowns alter zebrafish biliary development in a manner compatible with an AGS phenocopy.
NIH ExPorter
NIH ExPorter