title: An evolutionarily conserved role for the aryl hydrocarbon receptor in the regulation of movement.
abstract: The BXD genetic reference population is a recombinant inbred panel descended from crosses between the C57BL/6 (B6) and DBA/2 (D2) strains of mice, which segregate for about 5 million sequence variants. Recently, some of these variants have been established with effects on general metabolic phenotypes such as glucose response and bone strength. Here we phenotype 43 BXD strains and observe they have large variation (-5-fold) in their spontaneous activity during waking hours. QTL analyses indicate that -40% of this variance is attributable to a narrow locus containing the aryl hydrocarbon receptor (Ahr), a basic helix-loop-helix transcription factor with well-established roles in development and xenobiotic metabolism. Strains with the D2 allele of Ahr have reduced gene expression compared to those with the B6 allele, and have significantly higher spontaneous activity. This effect was also observed in B6 mice with a congenic D2 Ahr interval, and in B6 mice with a humanized AHR allele which, like the D2 allele, is expressed much less and has less enzymatic activity than the B6 allele. Ahr is highly conserved in invertebrates, and strikingly inhibition of its orthologs in D. melanogaster and C. elegans (spineless and ahr-1) leads to marked increases in basal activity. In mammals, Ahr has numerous ligands, but most are either non-selective (e.g. resveratrol) or highly toxic (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)). Thus, we chose to examine a major environmental influence--long term feeding with high fat diet (HFD)--to see if the effects of Ahr are dependent on major metabolic differences. Interestingly, while HFD robustly halved movement across all strains, the QTL position and effects of Ahr remained unchanged, indicating that the effects are independent. The highly consistent effects of Ahr on movement indicate that changes in its constitutive activity have a role on spontaneous movement and may influence human behavior.
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.affiliation: Laboratory of Systems Biology and Genetics, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Frochaux
authors.affiliation: Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Pénélope A
authors.initials: PA
authors.lastname: Andreux
authors.affiliation: Laboratory of Systems Biology and Genetics, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Bart
authors.initials: B
authors.lastname: Deplancke
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D018336:Receptors, Aryl Hydrocarbon