Pericentral activity of alpha-fetoprotein enhancer 3 and glutamine synthetase upstream enhancer in the adult liver are regulated by β-catenin in mice

Authors

  • Erica L. Clinkenbeard,

    Corresponding author
    1. Department of Microbiology, Immunology, and Molecular Genetics, Lexington, KY
    • Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536
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    • fax: 859-257-8994

  • James E. Butler,

    1. Department of Microbiology, Immunology, and Molecular Genetics, Lexington, KY
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    • Potential conflict of interest: Nothing to report.

  • Brett T. Spear

    1. Department of Microbiology, Immunology, and Molecular Genetics, Lexington, KY
    2. Markey Cancer Center, University of Kentucky, Lexington, KY
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  • These authors contributed equally to this work.

Abstract

We previously showed that mouse alpha-fetoprotein (AFP) enhancer 3 activity is highly restricted to pericentral hepatocytes in the adult liver. Here, using transgenic mice, we show that the upstream enhancer of the rat glutamine synthetase gene is also active, specifically in pericentral regions. Activity of both enhancers is lost in the absence of β-catenin, a key regulator of zonal gene expression in the adult liver. Both enhancers contain a single, highly conserved T-cell factor/lymphoid enhancer factor binding site that is required for responsiveness to β-catenin. We also show that endogenous AFP messenger RNA levels in the perinatal liver are lower when β-catenin is reduced. Conclusion: These data identify the first distinct zonally active regulatory regions required for β-catenin responsiveness in the adult liver, and suggest that postnatal AFP repression and the establishment of zonal regulation are controlled, at least in part, by the same factors. (HEPATOLOGY 2012;56:1892–1901)

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