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Conditional knockout mice, based on the Cre-loxP system, are a widely used model for examining organ-specific gene functions. To date, efficient hepatocyte-specific knockout has been reported in many different models, but little attention has been paid to the long-term stability of the recombination efficiency. In the present study, we characterizedAlb-Cre;Ctnnb1flox/flox‘hepatocyte-specificCtnnb1knockout’ mice of different ages to test whether efficient recombination is maintained over time. At 2 months of age, the knockout mouse livers achieved efficient deletions of β-catenin in hepatocytes. However, as the mice aged, the reappearance and expansion of β-catenin-expressing hepatocytes were observed. In 1-year-old mice, a significant proportion of the pericentral hepatocytes in the knockout mouse livers were replaced with β-catenin-positive hepatocytes, whereas the periportal hepatocytes mostly remained β-catenin-negative. Furthermore, most of the 1-year-old mice spontaneously developed hepatocellular adenomas and carcinomas that were positive for β-catenin and overexpressed glutamine synthetase and Slc1a2, both of which are hallmarks of active β-catenin signaling. Sequencing analysis revealed that theCtnnb1alleles were not inactivated but had activating mutations in these tumors. The present study suggests that recombination efficiency should be carefully examined when hepatocyte-specific knockout mice of different ages are analyzed. In addition, illegitimate deletion mutations should be recognized as potential adverse effects of the Cre-loxP system.

carcinogenesis

Hepatomas with activating               Ctnnb1               mutations in ‘              Ctnnb1              -deficient’ livers: a tricky aspect of a conditional knockout mouse model