A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish.
A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish.
复制标题
前蛋白转化酶基因 Furinb 的错义突变会导致斑马鱼肝脏发育过程中的肝囊肿发生。
DOI：
10.1002/hep4.2038
复制
发表时间：
2022-11
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
--
作者：
肝囊肿是肝脏中充满液体的病变，估计有 5% 的人群会出现。它们可能会导致肝肿大和腹痛。进展为继发性纤维化、肝硬化或胆管癌可导致发病和死亡。先前对患者和啮齿动物模型的研究表明，肝囊肿的形成与胆管细胞增殖和液体分泌增加有关，部分原因是初级纤毛受损。先天性肝囊肿被认为起源于胆管发育缺陷，但其潜在机制尚不完全清楚。在正向遗传筛选中，我们发现了一种在幼虫阶段发育出肝囊肿的斑马鱼突变体。囊肿的形成并非由于胆管细胞增殖、胆汁分泌的变化或初级纤毛的损伤所致。相反，延时实时成像数据显示，突变胆管细胞由于运动和突出活动缺陷而未能形成互连胆管。因此，免疫染色显示突变胆管细胞中肌动蛋白和微管细胞骨架紊乱。通过全基因组测序，我们确定突变体的囊性表型是由编码前蛋白转化酶的furinb基因的错义突变引起的。该突变改变了 Furinb 的定位并引起内质网 (ER) 应激。使用 ER 应激抑制剂 4-苯基丁酸治疗可以抑制囊性表型，而使用 ER 应激诱导剂衣霉素治疗则可以加剧囊性表型。突变的肝脏还表现出哺乳动物雷帕霉素靶点（mTOR）信号传导的增加。 mTOR 抑制剂治疗至少部分通过减少内质网应激来阻止囊肿形成。结论：我们的研究建立了研究肝囊肿发生的脊椎动物模型，并阐明了内质网应激在疾病发病机制中的作用。在正向遗传筛选中，我们发现了第一个在肝脏发育过程中形成肝囊肿的斑马鱼基因突变体。这些动物的囊肿发生是由于furinb 基因的错义突变造成的。该突变改变了 Furinb 蛋白的表达，随后诱导内质网应激，损害胆管细胞的行为。
Hepatic cysts are fluid‐filled lesions in the liver that are estimated to occur in 5% of the population. They may cause hepatomegaly and abdominal pain. Progression to secondary fibrosis, cirrhosis, or cholangiocarcinoma can lead to morbidity and mortality. Previous studies of patients and rodent models have associated hepatic cyst formation with increased proliferation and fluid secretion in cholangiocytes, which are partially due to impaired primary cilia. Congenital hepatic cysts are thought to originate from faulty bile duct development, but the underlying mechanisms are not fully understood. In a forward genetic screen, we identified a zebrafish mutant that developed hepatic cysts during larval stages. The cyst formation was not due to changes in biliary cell proliferation, bile secretion, or impairment of primary cilia. Instead, time‐lapse live imaging data showed that the mutant biliary cells failed to form interconnecting bile ducts because of defects in motility and protrusive activity. Accordingly, immunostaining revealed a disorganized actin and microtubule cytoskeleton in the mutant biliary cells. By whole‐genome sequencing, we determined that the cystic phenotype in the mutant was caused by a missense mutation in the furinb gene, which encodes a proprotein convertase. The mutation altered Furinb localization and caused endoplasmic reticulum (ER) stress. The cystic phenotype could be suppressed by treatment with the ER stress inhibitor 4‐phenylbutyric acid and exacerbated by treatment with the ER stress inducer tunicamycin. The mutant liver also exhibited increased mammalian target of rapamycin (mTOR) signaling. Treatment with mTOR inhibitors halted cyst formation at least partially through reducing ER stress. Conclusion: Our study has established a vertebrate model for studying hepatic cystogenesis and illustrated the contribution of ER stress in the disease pathogenesis. In a forward genetic screen, we identified the first zebrafish genetic mutant that develops hepatic cysts during liver development. Cystogenesis in these animals is due to a missense mutation in the furinb gene. The mutation alters Furinb protein expression that subsequently induces endoplasmic reticulum stress to impair biliary cell behaviors.
登录
查看更多内容
影响因子：
56.9
作者：
Mochizuki, T;Wu, GQ;Somlo, S
通讯作者：
Somlo, S
影响因子：
2.6
作者：
Parsons, Michael J.;Pisharath, Harshan;Yusuff, Shamila;Moore, John C.;Siekmann, Arndt F.;Lawson, Nathan;Leach, Steven D.
通讯作者：
Leach, Steven D.
影响因子：
4.8
作者：
Essalmani, Rachid;Susan-Resiga, Delia;Prat, Annik
通讯作者：
Prat, Annik
影响因子：
4.8
作者：
Noda, T;Ohsumi, Y
通讯作者：
Ohsumi, Y
DOI：
10.1002/dvdy.22220
发表时间：
2010-03
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
--
作者：
Lorent K;Moore JC;Siekmann AF;Lawson N;Pack M
通讯作者：
Pack M