Congenital biliary atresia is correlated with disrupted cell junctions and polarity caused by Cdc42 insufficiency in the liver

Theranostics. 2021 May 24;11(15):7262-7275. doi: 10.7150/thno.49116. eCollection 2021.


Rationale: Congenital biliary atresia (BA) is a destructive obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. However, the cause of BA is largely unknown. Methods: We explored the cell junctions and polarity complexes in early biopsy BA livers by immunofluorescence staining and western blot. Cdc42, as a key cell junction and polarity regulator, was found dramatically decreased in BA livers. Therefore, in order to investigate the role of Cdc42 in BA development, we constructed liver-specific and tamoxifen induced cholangiocyte-specific Cdc42 deleted transgenic mice. We further evaluated the role of bile acid in aggravating biliary damage in Cdc42 insufficient mouse liver. Results: We found a dramatic defect in the assembly of cell junctions and polarity complexes in both cholangiocytes and hepatocytes in BA livers. This defect was characterized by the disordered location of cell junction proteins, including ZO1, β-catenin, E-cadherin and claudin-3. Cdc42 and its active form, Cdc42-GTP, which serves as a small Rho GTPase to orchestrate the assembly of polarity complexes with Par6/Par3/αPKC, were substantially reduced in BA livers. Selective Cdc42 deficiency in fetal mouse cholangiocytes resulted in histological changes similar to those found in human BA livers, including obstruction in both the intra- and extrahepatic bile ducts, epithelial atrophy, and the disruption of cell junction and polarity complexes. A reduction in bile acids notably improved the histology and serological indices in Cdc42-mutant mice. Conclusion: Our results illustrate that BA is closely correlated with the impaired assembly of cell junction and polarity complexes in liver cells, which is likely caused by Cdc42 insufficiency and aggravated by bile acid corrosion.

Keywords: Cdc42; bile acids; biliary atresia; cell polarity; epithelial junction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biliary Atresia* / genetics
  • Biliary Atresia* / metabolism
  • Biliary Atresia* / pathology
  • Female
  • Genetic Diseases, Inborn* / genetics
  • Genetic Diseases, Inborn* / metabolism
  • Genetic Diseases, Inborn* / pathology
  • Humans
  • Infant
  • Intercellular Junctions* / genetics
  • Intercellular Junctions* / metabolism
  • Intercellular Junctions* / pathology
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • cdc42 GTP-Binding Protein / deficiency*
  • cdc42 GTP-Binding Protein / metabolism


  • Cdc42 protein, mouse
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein