Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation

• Published in: Disease models & mechanisms Vol. 16; no. 10
• Main Authors: Ali, Rouknuddin Q, Meyer-Miner, Anne, David-Rachel, Marie, Lee, Fiona J H, Wilkins, Benjamin J, Karpen, Saul J, Ciruna, Brian, Ghanekar, Anand, Kamath, Binita M
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.10.2023; The Company of Biologists
• Subjects: Abnormalities, Multiple; Animals; bile duct; Biliary Atresia; Biliary Tract; ciliopathy; crispr/cas9; laterality; Membrane Proteins - genetics; ped6; Spleen; Zebrafish - genetics; Ciliopathy; PED6; CRISPR/Cas9; Laterality; Bile duct
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.049326

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.