Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy.
Recent studies have suggested that beta-catenin is involved in the regulation of hepatocyte proliferation in multiple contexts, including organ development and tumorigenesis. We explored the role of beta-catenin during liver regeneration using T cell factor/lymphoid enhancer factor (TCF/LEF)-reporter mice (TOPGal mice) and liver-specific beta-catenin knockout mice. Liver-specific beta-catenin knockout mice showed a delayed onset of DNA synthesis after hepatectomy, whereas recovery of liver mass was not affected. Among putative beta-catenin target genes examined, the induction of Ccnd1 expression was reduced, whereas the expression of Myc and Egfr was unaffected. Furthermore, cyclin D1 protein levels were not induced, and the expression of cyclins A, E, and proliferating cell nuclear antigen was delayed. Intriguingly, the analysis of TOPGal mice showed that hepatocytes with active TCF/LEF transcription are confined to the pericentral zone and are not increased in number during regeneration, indicating an uncoupling between beta-catenin/TCF signaling activity and hepatocyte proliferation.


CONCLUSIONS
Our results indicate that beta-catenin is critical for the proper regulation of hepatocyte proliferation during liver regeneration; however, the activity of beta-catenin/TCF signaling does not correlate with hepatocyte proliferation, suggesting that this regulation might be indirect/secondary.
Sekine
Shigeki
S
Diabetes Center, Department of Medicine, Division of Transplantation, University of California San Francisco, San Francisco, CA 94143, USA.
Gutiérrez
Pedro J A
PJ
Lan
Billy Yu-Ang
BY
Feng
Sandy
S
Hebrok
Matthias
M
D000818:Animals; D049109:Cell Proliferation; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
D016213:Cyclins; D051820:TCF Transcription Factors; D051176:beta Catenin; D004247:DNA