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Am J Physiol Gastrointest Liver Physiol 292: G1578-G1585, 2007. First published March 1, 2007; doi:10.1152/ajpgi.00359.2006
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LIVER AND BILIARY TRACT

beta-Catenin is critical for early postnatal liver growth

Udayan Apte,1 Gang Zeng,1 Michael D. Thompson,1 Peggy Muller,1 Amanda Micsenyi,1 Benjamin Cieply,1 Klaus H. Kaestner,3 and Satdarshan P. S. Monga1,2

1Department of Pathology and 2Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh; and 3Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Submitted 3 August 2006 ; accepted in final form 23 February 2007

The Wnt/beta-catenin pathway plays an important role in embryonic liver development, morphogenesis, and organogenesis. Here, we report on the activation of beta-catenin during early postnatal liver growth. Modulation of beta-catenin expression was studied in CD-1 mice livers over a time course of 0 to 30 postnatal days (PD) and 3 mo. Increases in total and active beta-catenin were observed in developing livers from PD 5 to 20. A concomitant increase in the beta-catenin-transcription factor (TCF) complex along with nuclear and cytoplasmic beta-catenin was also evident, which coincided with ongoing hepatocyte proliferation by PCNA immunohistochemistry. This activation of beta-catenin was multifactorial, including cyclical inhibition of glycogen synthase kinase-3beta, suppression of casein kinase-II{alpha}, and a transient increase in beta-catenin gene expression. Coprecipitation experiments revealed the formation of the beta-catenin-cadherin complex at PD 5, whereas adequate beta-catenin-c-Met complex at the hepatocyte membrane did not form until PD 20, which might be contributing to the free beta-catenin pool during early postnatal growth. Furthermore, beta-catenin liver-specific knockout mice exhibited smaller livers at PD 30, secondary to diminished hepatocyte proliferation. These data indicate that the activation of beta-catenin is critical for early postnatal liver growth and development.

glycogen synthase kinase-3beta; casein kinase II{alpha}; hepatocyte proliferation; transcription factor; Met



Address for reprint requests and other correspondence: S. P. S. Monga, Depts. of Pathology and Medicine, Univ. of Pittsburgh School of Medicine, 200 Lothrop St., S-421 BST, Pittsburgh, PA 15216 (e-mail: smonga+{at}pitt.edu)




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