Conditional deletion of β-catenin reveals its role in liver growth and regeneration

Background & Aims: The Wnt/beta-catenin pathway plays a role in liver growth and development. To address this conclusively, we used a conditional knockout approach to delete beta-catenin in the liver. Methods: Floxed beta-catenin (exons 2-6) mice were intercrossed with Albumin-Cre recombinase transgenic mice; considerable beta-catenin deletion was evident IS days after birth by Western blot and immunohistochemistry analyses. Results: Although these mice were viable, there was a significant decrease in their liver weight/body weight ratio by 14% at I month and 28%-3S% by 2-6 months of age, which was sustained throughout their normal life span. There was an accompanying decrease in basal hepatocyte proliferation showed by Ki-67 staining. Additional analysis revealed several known and novel genes to be down-regulated in these mice that play a role in normal liver homeostasis. When subjected to two-thirds partial hepatectomy, the Ctnnb1(loxp/loxp); Alb-Cre(+/-) mice were sick and lethargic, especially during the first: 2-3 days only. These mice display a 2-fold decrease in the number of Ki-67- or PCNA-positive cells at the time of peak hepatocyte proliferation at 40 hours, which coincided with decreased cyclin A, D, and E expression. However, a rebound increase in hepatocyte proliferation was evident in the knockout mice at 3 days. Also, increased apoptosis was observed in the knockout livers during regeneration at all stages. Conclusions: Thus, beta-catenin is essential for normal liver growth and development. Also, although regeneration is delayed in the absence of beta-catenin, it does occur suboptimally, showing its redundancy in the liver.