Generation of an Allelic Series at the Ahr Locus Using an Edited Recombinant Approach. (22nd January 2021)

• Record Type: Journal Article
• Authors: Wilson, Rachel H; Carney, Patrick R; Glover, Edward; Parrott, Jessica C; Rojas, Brenda L; Moran, Susan M; Yee, Jeremiah S; Nukaya, Manabu; Goetz, Nicholas A; Rubinstein, Clifford D; Krentz, Kathy J; Xing, Yongna; Bradfield, Christopher A
• Is Part Of: Toxicological sciences. Volume 180:Number 2(2021)
• Page Start: 239
• Page End: 251
• Publication Date: 2021-01-22
• Subjects: aryl hydrocarbon receptor -- AHR -- conditional allele -- mouse model -- dioxin -- xenobiotics -- receptors -- CRISPR -- PAS -- dioxin receptor; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfab005
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a member of the PER-ARNT-SIM (PAS) superfamily of environmental sensors. The AHR is involved in a series of biological processes including adaptive metabolism of xenobiotics, toxicity of certain environmental pollutants, vascular development, fertility, and immune function. Mouse models, including the Ahr null and Ahr conditional null (Ahr fx ) mice, are widely used for the study of AHR-mediated biology and toxicity. The Ahr conditional null mouse harbors the low-affinity Ahr d allele that exhibits approximately a 10-fold lower binding affinity for certain xenobiotic AHR ligands than the widely used C57BL/6 mouse that harbors the higher affinity Ahr b1 allele. Here, we report a novel mouse model that introduces a V375A polymorphism that converts the low-affinity allele into a high-affinity allele, offering a more sensitive conditional model. In the generation of this novel conditional allele, two additional mutants arose, including a 3-bp deletion in the PAS-B domain ( Ahr NG367R ) and an early termination codon in the PAS-B domain ( Ahr Ter383 ). The Ahr NG367R allele presents as a phenocopy of the null and the Ahr Ter383 allele presents as an antimorph when assessing for the ductus venosus and liver lobe weight endpoints. These new models represent a series of tools that will be useful in further characterizing AHR biology.