IDENTIFICATION OF GENE(S) RESPONSIBLE FOR ALAGILLE SYNDR

我们早些时候已经表明，编码Notch受体配体的Jagged1（JAG1）基因突变是Alagille综合征（AGS）的原因，这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。编码锯齿和三角洲家庭的其他成员的基因也进行了表征。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。表征了三种锯齿状蛋白，称为锯齿状蛋白1、2和3，沿着它们的染色体位置和表达模式。它们（异位）表达在斑马鱼胚胎发育过程中的作用和在具有神经原性表型的mib突变体中的作用已经被研究。锯齿状RNA的异位表达导致野生型和mib突变型胚胎中神经元的减少。既然mib基因已经被鉴定出来，我们就可以了解jagged和mib基因在Notch通路中的作用。反义寡核苷酸（Morpholino衍生物）可有效降低斑马鱼中基因的表达，我们正在研究阻断锯齿功能对斑马鱼发育的影响。

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.