β-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development
β-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development
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DOI：
10.1002/hep.22225
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发表时间：
2008-05-01
期刊：
影响因子：
13.5
通讯作者：
Monga, Satdarshan P. S.
中科院分区：
文献类型：
--
作者：
Tan, Xinping;Yuan, Youzhong;Monga, Satdarshan P. S.
β-连环蛋白是经典Wnt通路的中心成分，在肝再生、生长和癌症的过程中起重要作用。以前，我们确定了在肝脏发育过程中β-连环蛋白的时间表达。在这里，我们的特点是肝脏表型，从成功删除β-连环蛋白在发育中的肝母细胞利用Foxa 3环化重组和benched-beta-catenin（外显子2至6）转基因小鼠。发育中的肝脏中β-连环蛋白的损失导致胚胎第12天（E12）后肝脏明显发育不全，致死发生在E17期左右。组织学检查显示，由于（1）氧化应激和细胞凋亡导致的细胞死亡增加，以及（2）继发于cydin-D1减少和增殖受损的扩增减少，肝细胞区室总体缺陷。此外，残余肝细胞表现出不成熟的表型，如高核质比、细胞极性差、缺乏糖原和关键肝脏富集转录因子（CCAAT增强子结合蛋白-α和肝细胞核因子-4 α）表达降低所示。还观察到原始胆管缺乏。虽然干细胞试验证明造血无内在缺陷，但扭曲的肝脏结构和肝细胞隔室缺陷导致内皮细胞组织缺陷，导致整体胎仔苍白。结论：β-连环蛋白调节肝脏形态发生过程中的多个关键事件，包括成肝细胞成熟、扩增和存活，使其对存活不可或缺。
beta-Catenin, the central component of the canonical Wnt pathway, plays important roles in the processes of liver regeneration, growth, and cancer. Previously, we identified temporal expression of beta-catenin during liver development. Here, we characterize the hepatic phenotype, resulting from the successful deletion of beta-catenin in the developing hepatoblasts utilizing Foxa3-cyclization recombination and floxed-beta-catenin (exons 2 through 6) transgenic mice. beta-Catenin loss in developing livers resulted in significantly underdeveloped livers after embryonic day 12 (E12) with lethality occurring at around E17 stages. Histology revealed an overall deficient hepatocyte compartment due to (1) increased cell death due to oxidative stress and apoptosis, and (2) diminished expansion secondary to decreased cydin-D1 and impaired proliferation. Also, the remnant hepatocytes demonstrated an immature phenotype as indicated by high nuclear to cytoplasmic ratio, poor cell polarity, absent glycogen, and decreased expression of key liver-enriched transcription factors: CCAAT-enhancer binding protein-alpha and hepatocyte nuclear factor-4 alpha. A paucity of primitive bile ducts was also observed. While the stem cell assays demonstrated no intrinsic defect in hematopoiesis, distorted hepatic architecture and deficient hepatocyte compartments resulted in defective endothelial cell organization leading to overall fetal pallor. Conclusion: beta-Catenin regulates multiple, critical events during the process of hepatic morphogenesis, including hepatoblast maturation, expansion, and survival, making it indispensable to survival.