Loss of TAZ after YAP deletion severely impairs foregut development and worsens cholestatic hepatocellular injury.
Loss of TAZ after YAP deletion severely impairs foregut development and worsens cholestatic hepatocellular injury.
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DOI：
10.1097/hc9.0000000000000220
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发表时间：
2023-09-01
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
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作者：
我们之前表明，早期肝脏发育（YAPKO）中yes相关蛋白1（YAP）的缺失会导致类似Alagille综合征的表型，导致肝内胆管发育失败、严重胆汁淤积以及肝细胞慢性适应以减少肝损伤。 TAZ 是 YAP 的旁系同源物，在 YAPKO 肝细胞中显着上调，并与 TEA 结构域家族成员 (TEAD) 转录因子相互作用，表明可能存在补偿活性。我们在早期肝脏发育过程中使用 Foxa3 启动子驱动 Cre 表达，删除了 Yap1 和 Wwtr1（编码 TAZ），类似于 YAPKO 小鼠，产生 YAP/TAZ 双敲除（DKO）和具有 TAZ 杂合性的 YAPKO（YAPKO TAZHET）。我们使用免疫组织化学、血清生物化学、胆汁酸分析和 RNA 测序对这些小鼠进行了评估。 DKO 小鼠是胚胎致死的，但它们的肝脏与 YAPKO 相似，表明死亡原因是肝外原因。雄性 YAPKO TAZET 小鼠胚胎也会死亡，但没有足够的样本来确定原因。然而，YAPKO TAZET 雌性小鼠存活下来，并且表型与 YAPKO 小鼠相似，胆汁酸亲水性增加，整体基因表达适应相似，但肝细胞损伤恶化。 YAPKO 中的 TAZ 杂合性影响了典型 YAP 靶标 Ctgf 和 Cyr61 的表达，我们发现调节细胞分裂和炎症信号传导途径的变化与肝细胞死亡、细胞周期和巨噬细胞招募的增加相关。 YAP 缺失（伴或不伴 TAZ 缺失）会中止胆道发育。 YAP 和 TAZ 在肝脏外前肠内胚层发育中起着相互依赖的关键作用，但它们对于肝细胞发育并不是必需的。 YAPKO 肝脏中的 TAZ 杂合性增加了慢性损伤情况下的细胞周期和炎症信号传导，突出显示对 TAZ 调节特别敏感的基因。
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity. We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing. DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment. YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
影响因子：
25.7
作者：
Wickline, Emily Diane;Awuah, Prince Kwaku;Behari, Jaideep;Ross, Mark;Stolz, Donna B.;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.