Conditional deletion of beta-catenin reveals its role in liver growth and regeneration.
OBJECTIVE
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 15 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 1 month and 28%-35% 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.
Tan
Xinping
X
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
Behari
Jaideep
J
Cieply
Benjamin
B
Michalopoulos
George K
GK
Monga
Satdarshan P S
SP
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000502:physiology; D049109:Cell Proliferation; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D006498:Hepatectomy; D008099:Liver / Q000254:growth & development*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
D015820:Cadherins; D018809:Proliferating Cell Nuclear Antigen; D051153:Wnt Proteins; D051176:beta Catenin; D003577:Cytochrome P-450 Enzyme System