title: Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins.
abstract: The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mechanisms whereby casein kinase1 (CK1) determines circadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period lengthened in CK1epsilon-/-, whereas CK1epsilon(tau/tau) shortened circadian period of behavior in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1epsilon(tau/tau) also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1epsilon(tau) acted by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Together, these whole-animal and biochemical studies explain how tau, as a gain-of-function mutation, acts at a specific circadian phase to promote degradation of PERIOD proteins and thereby accelerate the mammalian clockwork in brain and periphery.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Larisa
authors.initials: L
authors.lastname: Logunova
authors.affiliation: MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Maywood
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Gallego
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Jake
authors.initials: J
authors.lastname: Lebiecki
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Brown
authors.affiliation: MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
authors.forename: Martin
authors.initials: M
authors.lastname: Sládek
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Andrei S
authors.initials: AS
authors.lastname: Semikhodskii
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Nicholas R J
authors.initials: NRJ
authors.lastname: Glossop
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Piggins
authors.affiliation: MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Chesham
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
authors.affiliation: Howard Hughes Medical Institute, Dept. of Neurobiology & Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.affiliation: Howard Hughes Medical Institute, Dept. of Neurobiology & Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke/NUS Graduate Medical School Singapore, 2 Jalan Bukit Merah, Singapore 169547.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.|MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
authors.affiliation: Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
authors.forename: Andrew S I
authors.initials: ASI
authors.lastname: Loudon
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000235:genetics*; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D056950:Period Circadian Proteins; D010766:Phosphorylation; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D013997:Time Factors; D016875:tau Proteins / Q000172:deficiency* / Q000378:metabolism* / Q000502:physiology
chemical_list: D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D016875:tau Proteins; D048149:Casein Kinase 1 epsilon