Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor.
The aryl hydrocarbon receptor (AHR) is known for its role in the adaptive and toxic responses to a large number of environmental contaminants, as well as its role in hepatovascular development. The classical AHR pathway involves ligand binding, nuclear translocation, heterodimerization with the AHR nuclear translocator (ARNT), and binding of the heterodimer to dioxin response elements (DREs), thereby modulating the transcription of an array of genes. The AHR has also been implicated in signaling events independent of nuclear localization and DNA binding, and it has been suggested that such pathways may play important roles in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report the generation of a mouse model that expresses an AHR protein capable of ligand binding, interactions with chaperone proteins, functional heterodimerization with ARNT, and nuclear translocation, but is unable to bind DREs. Using this model, we provide evidence that DNA binding is required AHR-mediated liver development, as Ahr(dbd/dbd) mice exhibit a patent ductus venosus, similar to what is seen in Ahr(-/-) mice. Furthermore, Ahr(dbd/dbd) mice are resistant to TCDD-induced toxicity for all endpoints tested. These data suggest that DNA binding is necessary for AHR-mediated developmental and toxic signaling.
Bunger
Maureen K
MK
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Wisconsin 53706, USA.
Glover
Edward
E
Moran
Susan M
SM
Walisser
Jacqueline A
JA
Lahvis
Garet P
GP
Hsu
Erin L
EL
Bradfield
Christopher A
CA
D016475:3T3 Cells; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism; D002972:Cleft Palate / Q000139:chemically induced / Q000196:embryology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D005326:Fetal Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006869:Hydronephrosis / Q000139:chemically induced / Q000196:embryology; D008099:Liver / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011169:Portal Vein / Q000002:abnormalities; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D002274:Carcinogens, Environmental; D002352:Carrier Proteins; D019363:Cytochrome P-450 CYP1A1; D004247:DNA; D005326:Fetal Proteins; D008869:Microtubule-Associated Proteins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C418485:TACC3 protein, mouse