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IFT‐A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease
Author(s) -
Wang Wei,
Pottorf Tana S,
Wang Henry H,
Dong Ruochen,
Kavanaugh Matthew A,
Cornelius Joseph T,
Dennis Katie L,
Apte Udayan,
Pritchard Michele T,
Sharma Madhulika,
Tran Pamela V
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5685
Subject(s) - knockout mouse , biology , cilium , polycystic liver disease , cholangiocyte , conditional gene knockout , medicine , endocrinology , autosomal dominant polycystic kidney disease , liver disease , pathology , biliary tract , biliary atresia , congenital hepatic fibrosis , cyst , phenotype , kidney , portal hypertension , microbiology and biotechnology , gene , receptor , cirrhosis , genetics , transplantation , liver transplantation
Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with autosomal dominant polycystic kidney disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport‐B (IFT‐B) complex genes in adult mouse models of ADPKD attenuates the severity of PKD and PLD. Here we examine the role of deletion of an IFT‐A gene, Thm1 , in PLD of juvenile and adult Pkd2 conditional knockout mice. Perinatal deletion of Thm1 resulted in disorganized and expanded biliary regions, biliary fibrosis, increased serum bile acids, and a shortened primary cilium on cytokeratin 19+ (CK19+) epithelial cells. In contrast, perinatal deletion of Pkd2 caused PLD, with multiple CK19+ epithelial cell‐lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knockout mice increased hepatomegaly, liver necrosis, as well as serum bilirubin and bile acid levels, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 alone in adult mice did not cause a biliary phenotype. Combined deletion of Pkd2 and Thm1 caused variable hepatic cystogenesis at 4 months of age, but differences in hepatic cystogenesis between Pkd2 ‐ and Pkd2;Thm1 knockout mice were not observed by 6 months of age. Similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2 conditional knockout cyst‐lining epithelial cells. Taken together, Thm1 is required for biliary tract development, and proper biliary development restricts PLD severity. Unlike IFT‐B genes, Thm1 does not markedly attenuate hepatic cystogenesis, suggesting differences in regulation of signaling and cystogenic processes in the liver by IFT‐B and ‐A. Notably, increased Notch signaling in cyst‐lining epithelial cells may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.