The After-Hours Mutant Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period
Sofia I. H. Godinho,1*
Elizabeth S. Maywood,2*
Linda Shaw,1*
Valter Tucci,1
Alun R. Barnard,1
Luca Busino,3
Michele Pagano,3
Rachel Kendall,1
Mohamed M. Quwailid,1
M. Rosario Romero,1
John O'Neill,2
Johanna E. Chesham,2
Debra Brooker,1
Zuzanna Lalanne,1
Michael H. Hastings,2
Patrick M. Nolan1
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.
1 Medical Research Council (MRC) Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
2 MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Road, Cambridge CB2 2QH, UK.
3 Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: p.nolan{at}har.mrc.ac.uk
