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

Gary E. Pickard, Patricia J. Sollars, Eugene M. Rinchik, Patrick M. Nolan, Maja Bucan

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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 τDD 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 τDD 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.

Original languageEnglish (US)
Pages (from-to)255-266
Number of pages12
JournalBrain Research
Volume705
Issue number1-2
DOIs
StatePublished - Dec 24 1995

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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