Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock

doi:10.1128/MCB.00338-09

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Molecular and Cellular Biology, July 2009, p. 3853-3866, Vol. 29, No. 14
0270-7306/09/$08.00+0 doi:10.1128/MCB.00338-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock ^,

Jean-Pierre Etchegaray,¹ Kazuhiko K. Machida,¹^,2 Elizabeth Noton,¹ Cara M. Constance,³^, Robert Dallmann,¹^, Marianne N. Di Napoli,³^,|| Jason P. DeBruyne,¹^,# Christopher M. Lambert,¹ Elizabeth A. Yu,¹^,2^,4 Steven M. Reppert,¹^,2 and David R. Weaver¹^,2^*

Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,¹ Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts 01605,² Department of Biology, College of the Holy Cross, Worcester, Massachusetts 01610,³ M.D./Ph.D. Program, University of Massachusetts Medical School, Worcester, Massachusetts 01605⁴

Received 16 March 2009/ Returned for modification 14 April 2009/ Accepted 28 April 2009

Both casein kinase 1 delta (CK1 ${delta}$ ) and epsilon (CK1 ${varepsilon}$ ) phosphorylatecore clock proteins of the mammalian circadian oscillator. Toassess the roles of CK1 ${delta}$ and CK1 ${varepsilon}$ in the circadian clock mechanism,we generated mice in which the genes encoding these proteins(Csnk1d and Csnk1e, respectively) could be disrupted using theCre-loxP system. Cre-mediated excision of the floxed exon 2from Csnk1d led to in-frame splicing and production of a deletionmutant protein (CK1 ${delta}$ ²). This product is nonfunctional. Mice homozygousfor the allele lacking exon 2 die in the perinatal period, sowe generated mice with liver-specific disruption of CK1 ${delta}$ . Inlivers from these mice, daytime levels of nuclear PER proteins,and PER-CRY-CLOCK complexes were elevated. In vitro, the half-lifeof PER2 was increased by $~$ 20%, and the period of PER2::luciferasebioluminescence rhythms was 2 h longer than in controls. Fibroblastcultures from CK1 ${delta}$ -deficient embryos also had long-period rhythms.In contrast, disruption of the gene encoding CK1 ${varepsilon}$ did not alterthese circadian endpoints. These results reveal important functionaldifferences between CK1 ${delta}$ and CK1 ${varepsilon}$ : CK1 ${delta}$ plays an unexpectedly importantrole in maintaining the 24-h circadian cycle length.

* Corresponding author. Mailing address: Department of Neurobiology, LRB-723, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. Phone: (508) 856-2495. Fax: (508) 856-6266. E-mail: david.weaver{at}umassmed.edu

Published ahead of print on 4 May 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Biology, Hiram College, Hiram,OH 44234.

Present address: Santhera Pharmaceuticals, Hammerstrasse 47,4410 Liestal, Switzerland.

^|| Present address: Jefferson Davis High School, Science Department,101 Quitman Street, Houston, TX 77009.

^# Present address: Institute for Translational Medicine and Therapeutics,University of Pennsylvania School of Medicine, 835 BRBII/III,421 Curie Blvd., Philadelphia, PA 19104.

Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock ,

Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock ^,