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Updated: Nov 8, 2025
Determining Bile Duct Density in the Mouse Liver
Published on: April 30, 2019
IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease
Wei Wang1, Tana S Pottorf1, Henry H Wang1
1Department of Anatomy and Cell Biology, The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
Insights
Deletion of the Thm1 gene impairs biliary tract development, worsening polycystic liver disease (PLD) in mice. Proper biliary development is key to restricting PLD severity, unlike intraflagellar transport-B genes.
Area of Science:
- Cell Biology
- Genetics
- Pathology
Background:
- Polycystic liver disease (PLD) is associated with autosomal dominant polycystic kidney disease (ADPKD) and causes significant morbidity.
- Intraflagellar transport-B (IFT-B) complex gene deletion attenuates polycystic kidney disease (PKD) and PLD severity in adult mouse models.
Purpose of the Study:
- To investigate the role of an intraflagellar transport-A (IFT-A) gene, Thm1, in the pathogenesis of PLD in juvenile and adult Pkd2 conditional knockout mice.
- To compare the effects of Thm1 deletion with Pkd2 deletion on liver pathology and signaling pathways.
Main Methods:
- Perinatal and adult deletion of Thm1 and Pkd2 genes in mouse models.
- Histological analysis of liver tissues to assess biliary regions, fibrosis, and cystogenesis.
- Measurement of serum bile acids and bilirubin levels.
- Analysis of primary cilium length and signaling pathways (Notch, ERK) in epithelial cells.
Main Results:
- Perinatal Thm1 deletion led to disorganized biliary regions, fibrosis, and elevated bile acids, indicating impaired biliary development.
- Perinatal Pkd2 deletion caused PLD with cysts, fibrosis, lengthened primary cilia, and increased Notch/ERK signaling.
- Combined perinatal deletion of Thm1 and Pkd2 exacerbated liver disease severity.
- Thm1 deletion alone in adult mice did not cause a biliary phenotype, but combined deletion showed variable cystogenesis.
- Increased Notch signaling was observed in cyst-lining epithelial cells, suggesting a role in hepatic cystogenesis.
Conclusions:
- Thm1 is essential for normal biliary tract development, and its proper function restricts PLD severity.
- Unlike IFT-B genes, Thm1 does not significantly attenuate hepatic cystogenesis, indicating distinct regulatory roles.
- Aberrant activation of Notch signaling in cyst-lining epithelial cells may promote hepatic cystogenesis, representing a potential therapeutic target for PLD.
Abstract:
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.
