Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome
Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome
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DOI：
10.1002/hep.30912
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发表时间：
2020-01-24
期刊：
影响因子：
13.5
通讯作者：
Jafar-Nejad, Hamed
中科院分区：
文献类型：
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作者：
Adams, Joshua M.;Huppert, Kari A.;Jafar-Nejad, Hamed
背景和目的Alagille综合征（ALGS）是一种以胆管（BD）缺失为特征的多系统发育障碍性疾病，主要由Notch配体锯齿状单倍不足1引起。ALGS中肝病的病程变化很大。然而，ALGS表型变异的遗传基础是未知的。先前的研究报道了转录因子SOX 9（性别决定区Y盒9）在Jag 1缺陷小鼠的胚胎晚期和新生儿肝脏中的表达减少。在这里，我们研究了改变Sox 9基因剂量对ALGS小鼠模型肝脏疾病严重程度的影响。方法和结果在Jag 1（+/-）肝脏中有条件地去除一个拷贝的Sox 9会损害胆管细胞的胆道承诺，并增强炎症反应和肝纤维化。在Jag 1（+/-）肝脏中Sox 9的两个拷贝的丢失进一步破坏了表型并导致部分致死性。墨水注射实验显示P30 Jag 1（+/-）肝脏周围的胆管树形成受损，5月龄时改善。Sox 9杂合性影响P30胆管树表型，并损害5月龄动物的部分恢复。值得注意的是，Sox 9过表达改善了Jag 1（+/-）小鼠的BD缺乏和肝脏表型，而没有异位肝细胞向胆管细胞转分化或长期肝脏异常。Notch 2在肝脏中的表达在Sox 9过表达后增加，并且Sox 9结合肝脏中的Notch 2调节区。组织学分析显示了肝脏中SOX 9表达的水平和模式与ALGS患者肝脏疾病的结果之间的相关性。结论我们的研究结果证实Sox 9是Jag 1（+/-）肝脏表型的剂量敏感性修饰剂，在胆道发育中具有许可作用。我们的数据进一步表明，SOX 9水平的肝脏特异性增加是ALGS中BD缺乏的潜在治疗方法。
Background and Aims Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y-box 9) in late embryonic and neonatal livers of Jag1-deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. Approach and Results Conditional removal of one copy of Sox9 in Jag1(+/-) livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1(+/-) livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1(+/-) livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5-month-old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1(+/-) mice without ectopic hepatocyte-to-cholangiocyte transdifferentiation or long-term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. Conclusions Our results establish Sox9 as a dosage-sensitive modifier of Jag1(+/-) liver phenotypes with a permissive role in biliary development. Our data further suggest that liver-specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.