After-Hours Mutant Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period

• Published in: Science (American Association for the Advancement of Science) 2007-05, Vol.316 (5826), p.897-900
• Main Authors: Godinho, Sofia I.H, Maywood, Elizabeth S, Shaw, Linda, Tucci, Valter, Barnard, Alun R, Busino, Luca, Pagano, Michele, Kendall, Rachel, Quwailid, Mohamed M, Romero, M. Rosario, O'Neill, John, Chesham, Johanna E, Brooker, Debra, Lalanne, Zuzanna, Hastings, Michael H, Nolan, Patrick M
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animal genetics; Animals; ARNTL Transcription Factors; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chlorocebus aethiops; Chronometry; Circadian rhythm; Circadian Rhythm - genetics; Classical genetics, quantitative genetics, hybrids; CLOCK Proteins; COS Cells; Crosses, Genetic; Cryptochromes; F-Box Proteins - genetics; F-Box Proteins - physiology; Female; Flavoproteins - genetics; Flavoproteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Genetic mutation; Genetics of eukaryotes. Biological and molecular evolution; Homozygotes; Liver; Liver - metabolism; Lung - metabolism; Male; Mammals; Messenger RNA; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Molecular Sequence Data; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Period Circadian Proteins; Phenotypes; Point Mutation; Proteins; Rodents; Suprachiasmatic Nucleus - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Vertebrata
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1141138

By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys³⁵⁸Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.