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Molecular Pharmacology Fast Forward
First published on July 31, 2008; DOI: 10.1124/mol.108.047068

0026-895X/08/7405-1367-1371$20.00
Mol Pharmacol 74:1367-1371, 2008

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A Hypomorphic Allele of Aryl Hydrocarbon Receptor-Associated Protein-9 Produces a Phenocopy of the Ahr-Null Mouse

Bernice C. Lin, Linh P. Nguyen, Jacqueline A. Walisser, and Christopher A. Bradfield

McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin

The aryl hydrocarbon receptor-associated protein-9 (ARA9) is a chaperone of the aryl hydrocarbon receptor (AHR). The AHR has been shown to play a late developmental role in the normal closure of a fetal hepatovascular shunt known as the ductus venosus (DV). Given that Ara9-null mice display early embryonic lethality, we generated a hypomorphic Ara9 allele (designated Ara9fxneo) that displays reduced ARA9 protein expression. In an effort to demonstrate the role of ARA9 protein in AHR-mediated DV closure, we used combinations of Ara9 wild-type [Ara9(+/+)], null [Ara9(-/-)], and hypomorphic [Ara9(fxneo/fxneo)] alleles to produce mice with a graded expression of the ARA9 protein. Liver perfusion studies demonstrated that although none of the Ara9(+/+) mice displayed a patent DV, the shunt was observed in 10% of the Ara9(+/fxneo) mice, 55% of the Ara9(+/-) mice, and 83% of the Ara9(fxneo/fxneo) mice. That expression level of ARA9 correlates with the frequency of a phenocopy of the Ahr-null allele supports the conclusion that the ARA9 protein is essential for AHR signaling during development.

Received for publication March 7, 2008.

Accepted for publication July 31, 2008.

Address correspondence to: Dr. Christopher Bradfield, 1400 University Ave., Madison, WI 53706. E-mail: bradfield{at}oncology.wisc.edu




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