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Laboratory of Metabolism National Cancer Institute Bethesda, Maryland 20892
To determine the function of the aryl hydrocarbon
receptor nuclear translocator (ARNT), a conditional gene knockout mouse
was made using the Cre-loxP system. Exon 6, encoding the conserved
basic-helix-loop-helix domain of the protein, was flanked by loxP
sites and introduced into the Arnt gene by standard gene
disruption techniques using embryonic stem cells. Mice homozygous for
the floxed allele were viable and had no readily observable phenotype.
The Mx1-Cre transgene, in which Cre is under control of the
interferon-
promoter, was introduced into the
Arnt-floxed mouse line. Treatment with
polyinosinic-polycytidylic acid to induce expression of Cre resulted in
complete disruption of the Arnt gene and loss of ARNT
messenger RNA (mRNA) expression in liver. To determine the role of ARNT
in gene control in the intact animal mouse liver, expression of target
genes under control of an ARNT dimerization partner, the aryl
hydrocarbon receptor (AHR), was monitored. Induction of CYP1A1, CYP1A2,
and UGT1*06 mRNAs by the AHR ligand
2,3,7,8-tetrachlorodibenzo-pdioxin was absent in
livers of Arnt-floxed/Mx1-Cre mice treated with
polyinosinic-polycytidylic. These data demonstrate that ARNT is
required for AHR function in the intact animal. Partial deletion of the
Arnt allele was found in kidney, heart, intestine, and
lung. Despite more than 80% loss of the ARNT expression in lung,
maximal induction of CYP1A1 was found, indicating that the expression
level of ARNT is not limiting to AHR signaling. Cobalt chloride
induction of the glucose transporter-1 and heme oxygenase-1 mRNAs was
also markedly abrogated in mice lacking ARNT expression, suggesting an
inhibition of HIF-1
activity. These studies establish a critical
role for ARNT in AHR and HIF-1 signal transduction in the intact
mouse.
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