Mutagenesis and behavioral screening for altered circadian activity identifies the mouse mutant, Wheels

• Published in: Brain research Vol. 705; no. 1; pp. 255 - 266
• Main Authors: Pickard, Gary E., Sollars, Patricia J., Rinchik, Eugene M., Nolan, Patrick M., Bucan, Maja
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 24.12.1995; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Behavior, Animal - physiology; Biological and medical sciences; Chromosome Mapping; Chronobiology; Circadian Rhythm - genetics; Fundamental and applied biological sciences. Psychology; Genotype; Light; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains - genetics; Motor Activity - genetics; Mutagenesis - physiology; Periodicity; Polymerase Chain Reaction; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Locomotion; Vertebrata; Regulation(control); Mammalia; Mouse; Rodentia; Biological rhythm; Behavior; Circadian rhythm
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/0006-8993(95)01171-4

The molecular processes underlying the generation of circadian behavior in mammals are virtually unknown. To identify genes that regulate or alter circadian activity rhythms, a mouse mutagenesis program was initiated in conjunction with behavioral screening for alterations in circadian period (τ), a fundamental property of the biological clock. Male mice of the inbred BALB/c strain, treated with the potent mutagen N-ethyl- N-nitrosourea were mated with wild-type hybrids. Wheel-running activity of ∼ 300 male progeny was monitored for 6–10 weeks under constant dark (DD) conditions. The τ DD of a single mouse (#187) was longer than the population mean by more than three standard deviations (24.20 vs. 23.32 ± 0.02 h; mean ± S.E.M.; n = 277). In addition, mouse #187 exhibited other abnormal phenotypes, including hyperactive bi-directional circling/ spinning activity and an abnormal response to light. Heterozygous progeny of the founder mouse, generated from outcrossings with wild-type C57BL/6J mice, displayed lengthened τ DD although ∼ 20% of the animals showed no wheel-running activity despite being quite active. Under light:dark conditions, all animals displaying circling behavior that ran in the activity wheels exhibited robust wheel-running activity at lights-ON and these animals also showed enhanced wheel-running activity in constant light conditions. The genetic dissection of the complex behavior associated with this mutation was facilitated by the previously described genetic mapping of the mutant locus causing circling behavior, designated Wheels (Whl), to the subcentromeric portion of mouse chromosome 4. In this report, the same locus is shown to be responsible for the abnormal responses to light and presumably for the altered circadian behavior. Characterization of the gene altered in the novel Whl mutation will contribute to understanding the molecular elements involved in mammalian circadian regulation.