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J. Biol. Chem., Vol. 282, Issue 49, 35924-35932, December 7, 2007

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Deletion of the Aryl Hydrocarbon Receptor-associated Protein 9 Leads to Cardiac Malformation and Embryonic Lethality^*

Bernice C. Lin, Ruth Sullivan, Youngsook Lee^¶, Susan Moran, Edward Glover, and Christopher A. Bradfield¹

From the McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, the University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, and the ^¶Department of Anatomy, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706

The aryl hydrocarbon receptor-associated protein 9, ARA9 (also known as XAP2 or AIP1), is a chaperone that is found in complexes with certain xenobiotic receptors, such as the aryl hydrocarbon receptor (AHR) and the peroxisome proliferator-activated receptor (PPAR). In an effort to better understand the physiological role of ARA9 outside of its role in xenobiotic signal transduction, we generated a null allele at the Ara9 locus in mice. Mice with a homozygous deletion of this gene die at various time points throughout embryonic development. Embryonic lethality is accompanied by decreased blood flow to head and limbs, as well as a range of heart deformations, including double outlet right ventricle, ventricular-septal defects, and pericardial edema. The early cardiovascular defects observed in Ara9-null mice suggest an essential role for the ARA9 protein in cardiac development. The observation that the developmental aberrations in Ara9-null mice are distinct from those observed for disrupted alleles at Ahr or Ppar indicates that the role of ARA9 in cardiac development is independent of its interactions with its known xenobiotic receptor partners.

Received for publication, July 3, 2007 , and in revised form, October 4, 2007.

^* This work was supported by National Institutes of Health Grants R01-ES006883, T32-CA009135, and P30-CA014520. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: McArdle Laboratory for Cancer Research, 1400 University Ave., Madison, WI 53706. Tel.: 608-262-1209; Fax: 608-262-2824; E-mail: bradfield{at}oncology.wisc.edu.

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