Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.
Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.
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DOI：
10.1242/dmm.049326
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发表时间：
2023-10-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
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胆道闭锁是一种纤维炎性新生儿疾病，目前尚无有效的治疗方法。一部分病例（10-20%）与侧侧缺陷有关-标记的胆道闭锁脾畸形（BASM）综合征。最近，BASM患者的全外显子组测序发现了PKD1L1的有害变异。PKD1L1参与左右轴的确定；然而，其在胆管细胞中的作用尚不清楚。我们利用CRISPR/Cas9诱变技术在斑马鱼中产生了pkd11hsc117等位基因，以确定Pkd1l1在胆道发育和功能中的作用。在受精后5天，评估野生型和突变型幼虫的侧边缺陷、胆道功能和胆道树结构。pkd11hsc117突变体幼虫表现出早期左右模式缺陷。47%的突变体的胆囊位于左侧，而野生型幼虫的这一比例为4%。与野生型幼虫（4%）相比，pkd11hsc117突变体（46%）胆囊中PED6的积累显著减少（PED6是肝胆功能的指标）。与野生型幼虫相比，pkd11hsc117幼虫表现出较少的胆道上皮细胞和降低的肝内胆道网络密度。这些数据强调了pkd1l1在斑马鱼胆道系统正常发育和功能中的重要作用，支持该基因作为BASM病因的作用。摘要：pkd1l1相关性胆道闭锁是一种严重的儿童肝脏疾病，目前尚无有效的治疗方法。斑马鱼pkd1l1的缺失导致肝脏胆管功能受损和发育异常。
Biliary atresia is a fibroinflammatory neonatal disease with no effective therapies. A subset of cases (10-20%) is associated with laterality defects – labeled biliary atresia splenic malformation (BASM) syndrome. Recently, whole-exome sequencing of patients with BASM identified deleterious variants in PKD1L1. PKD1L1 is involved in left-right axis determination; however, its role in cholangiocytes is unknown. We generated the pkd1l1hsc117 allele using CRISPR/Cas9 mutagenesis in zebrafish to determine the role of Pkd1l1 in biliary development and function. Wild-type and mutant larvae were assessed for laterality defects, biliary function and biliary tree architecture at 5 days post fertilization. pkd1l1hsc117 mutant larvae exhibited early left-right patterning defects. The gallbladder was positioned on the left in 47% of mutants compared to 4% of wild-type larvae. Accumulation of PED6 in the gallbladder, an indicator of hepatobiliary function, was significantly reduced in pkd1l1hsc117 mutants (46%) compared to wild-type larvae (4%). pkd1l1hsc117 larvae exhibited fewer biliary epithelial cells and reduced density of the intrahepatic biliary network compared to those in wild-type larvae. These data highlight the essential role of pkd1l1 in normal development and function of the zebrafish biliary system, supporting a role for this gene as a cause of BASM. Summary: PKD1L1-linked biliary atresia is a serious childhood liver disease with no effective therapies. Deletion of zebrafish pkd1l1 results in impaired function and abnormal development of bile ducts in the liver.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.2
作者：
Braun DA;Hildebrandt F
通讯作者：
Hildebrandt F
影响因子：
9.8
作者：
Bao, Zhiwei;Zhao, Yao;Jin, Yuanxiang
通讯作者：
Jin, Yuanxiang
影响因子：
2.5
作者：
Masyuk, Anatoliy I.;Masyuk, Tatyana V.;LaRusso, Nicholas F.
通讯作者：
LaRusso, Nicholas F.
影响因子：
21.3
作者：
Borovina, Antonia;Superina, Simone;Ciruna, Brian
通讯作者：
Ciruna, Brian