Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in biliary epithelial cells

Area of Science:

• Genetics
• Developmental Biology
• Hepatology

Background:

• Syndromic biliary atresia is a cholangiopathy with unknown etiology, characterized by extrahepatic bile duct (EHBD) fibro-obliteration and congenital malformations.
• Genetic syndromes offer insights into disease mechanisms, prompting investigation into the role of Pkd1l1 in syndromic biliary atresia.

Purpose of the Study:

• To investigate the role of the Pkd1l1 gene in the pathophysiology of syndromic biliary atresia.
• To establish and characterize a Pkd1l1 knockout mouse model for studying biliary atresia.

Main Methods:

• Generated constitutive and conditional Pkd1l1 knockout mice.
• Assessed congenital anomalies, EHBD and liver pathology, biliary drainage, gene expression, and biliary epithelial cell turnover.
• Utilized DDC diet treatment and GLI1 inhibition to evaluate disease progression and therapeutic targets.

Main Results:

• Pkd1l1-deficient mice exhibited laterality defects, hypertrophic and fibrotic EHBDs with delayed drainage, and liver pathology including ductular reaction and fibrosis.
• Loss of Pkd1l1 led to altered expression of fibrosis and ciliary signaling genes, with reduced primary cilia on biliary epithelial cells.
• Inhibition of GLI1 recapitulated Pkd1l1-deficiency phenotypes, suggesting disrupted ciliary signaling as a key mechanism.

Conclusions:

• Pkd1l1 deficiency causes laterality defects and EHBD fibro-proliferation via disrupted ciliary signaling, phenocopying syndromic biliary atresia.
• Pkd1l1-deficient mice serve as an authentic genetic model for studying biliary atresia pathogenesis.
• This research identifies ciliopathy as a potential etiology for biliary atresia and offers a model for developing novel therapeutic strategies.