IDENTIFICATION OF THE GENE(S) RESPONSIBLE FOR ALAGILLESY

编码Notch受体配体的Jagged1 （JAG1）基因的突变是导致阿拉吉尔综合征（AGS）的原因。AGS是一种影响多器官系统的发育障碍，包括肝脏、心脏、眼睛、面部和脊椎。在Notch通路的许多其他成员中，人类疾病和小鼠表型相关的突变已经被描述。由于斑马鱼是脊椎动物发育的优秀模型，我们从斑马鱼中分离并表征了Jagged同源基因，以探索它们在发育性疾病（如Alagille综合征）中的作用。三个锯齿被称为锯齿1,2和3的特征，以及它们的染色体位置和表达。它们（异位）表达在斑马鱼胚胎发育和具有神经源性表型的mib突变体中的影响已被研究。锯齿状rna的异位表达导致野生和mib突变胚胎神经元的减少。定位克隆表明，mib是Notch通路上的一个新基因，是一种环E3泛素连接酶，在泛素化过程中起关键作用。为Jaggeds 1、2和3生成的反义寡核苷酸（Morpholino衍生物）正被用于探索它们在肝脏发育中的作用，并更好地了解Alagille综合征。

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.