Human Jagged 1 mutants cause liver defect in Alagille syndrome by overexpression of hepatocyte growth factor.
Human Jagged 1 mutants cause liver defect in Alagille syndrome by overexpression of hepatocyte growth factor.
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DOI：
10.1016/j.jmb.2005.11.097
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发表时间：
2006-02
影响因子：
5.6
通讯作者：
Zeng‐rong Yuan;N. Kobayashi;T. Kohsaka
中科院分区：
文献类型：
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作者：
Zeng‐rong Yuan;N. Kobayashi;T. Kohsaka
阿拉吉尔综合征（AGS，MIM 118450）是一种常染色体显性遗传病。小叶间胆管缺乏是主要异常之一。为了探讨人类Jagged 1基因（JAG1，MIM 601920）突变导致肝脏缺陷的分子机制，我们研究了JAG1对肝细胞生长因子基因（HGF）的基因调控。通过体外将野生型和突变型JAG1转染至COS-7细胞中，我们发现HGF是JAG1下游的靶基因。野生型 JAG1 对 HGF 表达具有抑制作用，而突变型 JAG1 可缓解这种抑制。突变型 JAG1 蛋白中的多个结构域破坏揭示了不同水平上对 HGF 表达的抑制作用降低。 JAG1 突变实际上会导致 HGF 过度表达。此外，JAG1 通过剂量依赖性调节控制 HGF 表达，Notch2 信号传导似乎介导 JAG1 功能。鉴于 HGF 在肝干细胞分化中发挥关键作用，HGF 的过度表达会影响 AGS 患者失衡的细胞命运决定。肝干细胞可能分化为更多的肝细胞，但更少的胆管细胞，从而导致AGS肝脏发育过程中小叶间胆管的缺乏。我们的新发现表明，JAG1 突变的剂量依赖性调节是 AGS 肝脏异常的基本机制。
Alagille syndrome (AGS, MIM 118450) is an autosomal dominant inherited disease. Paucity of interlobular bile ducts is one of the major abnormalities. To explore the molecular mechanism by which mutation in the human Jagged 1 gene (JAG1, MIM 601920) causes liver defects, we investigated the gene regulation of JAG1 to hepatocyte growth factor gene (HGF). By transfecting wild-type and mutant JAG1 into COS-7 cells in vitro, we found that HGF is a target gene of JAG1 downstream. Wild-type JAG1 is inhibitory for HGF expression and mutant JAG1s relieve the inhibition. Several domain disruptions in mutant JAG1 protein reveal a reduced inhibition to HGF expression at different levels. JAG1 mutations actually result in HGF overexpression. Furthermore, JAG1 controls HGF expression by a dosage-dependent regulation and Notch2 signaling seems to mediate JAG1 function. Given that HGF plays a critical role in differentiation of hepatic stem cells, overexpression of HGF acts on off-balanced cell fate determination in AGS patients. Hepatic stem cells may differentiate towards more hepatocytes but less biliary cells, thus causing the paucity of interlobular bile ducts in liver development of AGS. Our novel findings demonstrated that dosage-dependent regulation by mutations of JAG1 is a fundamental mechanism for liver abnormality in AGS.