Apc tumor suppressor gene is the "zonation-keeper" of mouse liver
Apc tumor suppressor gene is the "zonation-keeper" of mouse liver
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DOI：
10.1016/j.devcel.2006.03.015
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发表时间：
2006-06-01
影响因子：
11.8
通讯作者：
Colnot, Sabine
中科院分区：
文献类型：
--
作者：
Benhamouche, Samira;Decaens, Thomas;Colnot, Sabine
肝脏基因沿门静脉中轴沿着差异表达的分子机制，允许代谢分区，知之甚少。我们在这里提供了令人信服的证据表明，Wnt/β-连环蛋白途径在肝脏分区中起着关键作用。首先，我们显示了激活的β-连环蛋白在静脉周围区域和门静脉周围肝细胞中的负调节因子Apc的互补定位。然后，我们分析了直接后果的肝脏诱导的APC中断或Wnt信号的阻断感染后的腺病毒编码Dkk 1，我们表明，Wntlo-连环蛋白信号反向控制静脉周围和门静脉周围的遗传程序。最后，我们发现门脉周围尿素循环和静脉周围谷氨酰胺合成系统的基因是β-连环蛋白信号传导的关键目标，并且氨代谢的扰动可能是导致肝脏靶向Apc丢失小鼠死亡的原因。从我们的研究结果，我们建议，APC是肝脏的“zonation-keeper”基因。
The molecular mechanisms by which liver genes are differentially expressed along a portocentral axis, allowing for metabolic zonation, are poorly understood. We provide here compelling evidence that the Wnt/beta-catenin pathway plays a key role in liver zonation. First, we show the complementary localization of activated beta-catenin in the perivenous area and the negative regulator Apc in periportal hepatocytes. We then analyzed the immediate consequences of either a liver-inducible Apc disruption or a blockade of Wnt signaling after infection with an adenovirus encoding Dkk1, and we show that Wntlo-catenin signaling inversely controls the perivenous and periportal genetic programs. Finally, we show that genes involved in the periportal urea cycle and the perivenous glutamine synthesis systems are critical targets of beta-catenin signaling, and that perturbations to ammonia metabolism are likely responsible for the death of mice with liver-targeted Apc loss. From our results, we propose that Apc is the liver "zonation-keeper" gene.