Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins.
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.
Meng
Qing-Jun
QJ
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Logunova
Larisa
L
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Maywood
Elizabeth S
ES
MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
Gallego
Monica
M
Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA.
Lebiecki
Jake
J
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Brown
Timothy M
TM
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Sládek
Martin
M
MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
Semikhodskii
Andrei S
AS
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Glossop
Nicholas R J
NRJ
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Piggins
Hugh D
HD
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Chesham
Johanna E
JE
MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Rd. Cambridge CB2 2QH, U.K.
Bechtold
David A
DA
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Yoo
Seung-Hee
SH
Howard Hughes Medical Institute, Dept. of Neurobiology & Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA.
Takahashi
Joseph S
JS
Howard Hughes Medical Institute, Dept. of Neurobiology & Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA.
Virshup
David M
DM
Program in Cancer and Stem Cell Biology, Duke/NUS Graduate Medical School Singapore, 2 Jalan Bukit Merah, Singapore 169547.
Boot-Handford
Raymond P
RP
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
Hastings
Michael H
MH
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.
Loudon
Andrew S I
ASI
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
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
D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D016875:tau Proteins; D048149:Casein Kinase 1 epsilon