Phenotype and growth behavior of residual β-catenin-positive hepatocytes in livers of β-catenin-deficient mice

Histochem Cell Biol. 2010 Nov;134(5):469-81. doi: 10.1007/s00418-010-0747-1. Epub 2010 Oct 1.


Signaling through the Wnt/β-catenin pathway is a crucial determinant of hepatic zonal gene expression, liver development, regeneration, and tumorigenesis. Transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) have proven their usefulness in elucidating these processes. We now found that a small number of hepatocytes escape the Cre-mediated gene knockout in that mouse model. The remaining β-catenin-positive hepatocytes showed approximately 25% higher cell volumes compared to the β-catenin-negative cells and exhibited a marker protein expression profile similar to that of normal perivenous hepatocytes or hepatoma cells with mutationally activated β-catenin. Surprisingly, the expression pattern was observed independent of the cell's position within the liver lobule, suggesting a malfunction of physiological periportal repression of perivenously expressed genes in β-catenin-deficient liver. Clusters of β-catenin-expressing hepatocytes lacked expression of the gap junction proteins Connexin 26 and 32. Nonetheless, β-catenin-positive hepatocytes had no striking proliferative advantage, but started to grow out on treatment with phenobarbital, a tumor-promoting agent known to facilitate the formation of mouse liver adenoma with activating mutations of Ctnnb1. Progressive re-population of Ctnnb1 knockout livers with wild-type hepatocytes was seen in aged mice with a pre-cirrhotic phenotype. In these large clusters of β-catenin-expressing hepatocytes, perivenous-specific gene expression was re-established. In summary, our data demonstrate that the zone-specificity of a hepatocyte's gene expression profile is dependent on the presence of β-catenin, and that β-catenin provides a proliferative advantage to hepatocytes when promoted with phenobarbital, or in a pre-cirrhotic environment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / pharmacology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation
  • Cell Separation
  • Cell Size
  • Connexins / deficiency
  • Cytochrome P-450 CYP2E1 / metabolism
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Glutamate-Ammonia Ligase / metabolism
  • Hepatocytes / metabolism
  • Hepatocytes / pathology*
  • Liver / drug effects
  • Liver / enzymology
  • Liver / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Phenobarbital / pharmacology
  • Phenotype
  • RNA, Messenger / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • CTNNB1 protein, mouse
  • Carcinogens
  • Connexins
  • RNA, Messenger
  • beta Catenin
  • Cytochrome P-450 CYP2E1
  • Glutamate-Ammonia Ligase
  • Phenobarbital