Basic—Liver, Pancreas, and Biliary TractLiver Zonation Occurs Through a β-Catenin–Dependent, c-Myc–Independent Mechanism
Section snippets
Mouse Lines
All experiments were performed under the UK Home Office guidelines. Outbred male mice from 6 to 12 weeks of age were segregated for the C57BJ and S129 genomes. The loxP flanked alleles used were as follows: Apc,18β-catenin,19c-Myc,20 and AhCre.19 To induce recombination, mice were given 3 daily intraperitoneal injections of β-napthoflavone (bNF) 80 mg/kg body weight and livers were harvested either 4 or 21 days after the first injection. Mice were humanely killed by a Schedule 1 procedure and
Ahcre Mice and Recombination
To investigate the role of β-catenin signaling in liver zonation, we took advantage of a system for introducing specific gene mutations into the epithelia of the adult murine liver by the transcriptional regulation of Cre recombinase. In a transgenic line (Ahcre), cre expression is inducible from a cytochrome P450 promoter element that is transcriptionally up-regulated in response to lipophilic xenobiotics such as bNF. We initially determined the efficiency of Cre-mediated recombination, Ahcre
Discussion
To elucidate the role of Wnt/β-catenin pathway in maintenance of the normal liver, we investigated the deletion of the signaling intermediates: Apc, β-catenin, and c-Myc alone and in combination.
Until recently, the molecular mechanisms responsible for maintenance of metabolic zonation in the liver were poorly understood. At least some of the gradients of function, such as those of carbohydrate and xenobiotic metabolism, are thought to be regulated by the gradients of oxygen and hormones that
Acknowledgments
ZDB and KRR contributed equally to this work.
The authors thank the Wellcome Trust and Cancer Research UK for financial support. We also thank Professor Wouter Lamers, Professor Satoshi Yamagoe, and Professor Magnus Ingelmann Sundberg for antibodies and Mark Bishop, Lucy Pietzka, Iryna Withington, and Derek Scarborough for technical assistance.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the Wellcome Trust and Cancer Research UK.