IDENTIFICATION OF THE GENE(S) RESPONSIBLE FOR ALAGILLE

编码Notch受体配体的Jagged1（JAG1）基因突变导致Alagille综合征（AGS）。AGS是一种影响多个器官系统的发育障碍，包括肝脏、心脏、眼睛、面部和椎骨。已经描述了Notch途径的许多其他成员中的人类疾病和小鼠表型相关突变。由于斑马鱼是脊椎动物发育的一个很好的模型，我们已经从斑马鱼中分离和鉴定了Jagged同源基因，以探索它们在发育疾病如Alagille综合征中的作用。三个锯齿状称为锯齿状1，2和3， 分离和表征，沿着它们的染色体定位和表达。锯齿状RNA的异位表达导致mib突变胚胎中神经元的减少，这些胚胎被认为在Notch信号传导中存在缺陷。定位克隆表明，mib是一个新的 Notch途径中的基因，其编码RING泛素连接酶，所述RING泛素连接酶是Delta有效激活Notch所必需的。它似乎通过促进Notch配体Delta的内吞作用来促进Notch受体的活化。针对锯齿状蛋白1、2和3产生的反义寡核苷酸（吗啉代衍生物）正被用于探索其在肝脏发育中的作用，这可能会更好地了解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 isolated and characterized, along with their chromosomal location and expression. Ectopic expression of jagged RNAs leads to a reduction of neurons in mib mutant embryos that are thought to have a deficit in Notch signalling. 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. It appears to facilitate activation of the Notch receptor by promoting the endocytosis of the Notch ligand, Delta. Antisense oligonucleotides (Morpholino derivatives) generated for Jaggeds 1, 2 and 3 are being used to explore their role in liver development, which may provide a better understanding of the Alagille syndrome.