Home LiteratureArticle Details
PMID: 9160755 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Positional cloning of the mouse circadian clock gene.

Cell ·Vol. 89 ·No. 4 ·1997-05-16 ·Pages 641-53

King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL, Turek FW, Takahashi JS

Abstract

We used positional cloning to identify the circadian Clock gene in mice. Clock is a large transcription unit with 24 exons spanning approximately 100,000 bp of DNA from which transcript classes of 7.5 and approximately 10 kb arise. Clock encodes a novel member of the bHLH-PAS family of transcription factors. In the Clock mutant allele, an A-->T nucleotide transversion in a splice donor site causes exon skipping and deletion of 51 amino acids in the CLOCK protein. Clock is a unique gene with known circadian function and with features predicting DNA binding, protein dimerization, and activation domains. CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism.

MeSH Terms
Amino Acid Sequence Animals Base Sequence CLOCK Proteins Chick Embryo Chromosome Mapping Circadian Rhythm/genetics Cloning, Molecular Conserved Sequence DNA Primers/genetics DNA, Complementary/genetics Dogs Drosophila/genetics Evolution, Molecular Humans Mice Molecular Sequence Data Mutation RNA, Messenger/genetics Sequence Homology, Amino Acid Trans-Activators/genetics
Chemicals
DNA Primers DNA, Complementary RNA, Messenger Trans-Activators CLOCK Proteins CLOCK protein, human Clock protein, mouse
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
King D P
National Science Foundation Center for Biological Timing, Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Zhao Y
Sangoram A M
Wilsbacher L D
Tanaka M
Antoch M P
Steeves T D
Vitaterna M H
Kornhauser J M
Lowrey P L
Turek F W
Takahashi J S
References (66)
66 references, click to expand
  1. Genetics and molecular analysis of circadian rhythms.
    Annu Rev Genet. 1996;30:579-601 PMID: 8982466
  2. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway.
    J Biol Chem. 1997 Mar 28;272(13):8581-93 PMID: 9079689
  3. Positional cloning and sequence analysis of the Drosophila clock gene, timeless.
    Science. 1995 Nov 3;270(5237):805-8 PMID: 7481771
  4. Tripping along the trail to the molecular mechanisms of biological clocks.
    Trends Neurosci. 1995 May;18(5):230-40 PMID: 7610493
  5. Antibodies to the period gene product of Drosophila reveal diverse tissue distribution and rhythmic changes in the visual system.
    Neuron. 1988 Apr;1(2):141-50 PMID: 3152288
  6. trachealess encodes a bHLH-PAS protein that is an inducer of tracheal cell fates in Drosophila.
    Genes Dev. 1996 Jan 1;10(1):93-102 PMID: 8557198
  7. The Drosophila bendless gene encodes a neural protein related to ubiquitin-conjugating enzymes.
    Neuron. 1993 Aug;11(2):253-66 PMID: 8394720
  8. Circadian rhythm mutations in Drosophila melanogaster affect short-term fluctuations in the male's courtship song.
    Proc Natl Acad Sci U S A. 1980 Nov;77(11):6729-33 PMID: 6779281
  9. PAS is a dimerization domain common to Drosophila period and several transcription factors.
    Nature. 1993 Jul 15;364(6434):259-62 PMID: 8391649
  10. Interpreting cDNA sequences: some insights from studies on translation.
    Mamm Genome. 1996 Aug;7(8):563-74 PMID: 8679005
  11. Isolation, characterization, and expression of cDNAs encoding the medaka (Oryzias latipes) ovarian follicle cytochrome P-450 aromatase.
    Mol Reprod Dev. 1996 Nov;45(3):285-90 PMID: 8916038
  12. Regulation of nuclear entry of the Drosophila clock proteins period and timeless.
    Neuron. 1996 Nov;17(5):911-20 PMID: 8938123
  13. Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector.
    Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8794-7 PMID: 1528894
  14. The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit.
    Genetics. 1997 Jul;146(3):1049-60 PMID: 9215907
  15. Construction of a mouse yeast artificial chromosome library in a recombination-deficient strain of yeast.
    Nat Genet. 1992 May;1(2):132-6 PMID: 1302006
  16. Circadian clock genes are ticking.
    Science. 1992 Oct 9;258(5080):238-40 PMID: 1384127
  17. A genetic map of the mouse suitable for typing intraspecific crosses.
    Genetics. 1992 Jun;131(2):423-47 PMID: 1353738
  18. Cloning of a factor required for activity of the Ah (dioxin) receptor.
    Science. 1991 May 17;252(5008):954-8 PMID: 1852076
  19. Yeast artificial chromosome libraries containing large inserts from mouse and human DNA.
    Proc Natl Acad Sci U S A. 1991 May 15;88(10):4123-7 PMID: 2034658
  20. Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL.
    Science. 1995 Nov 3;270(5237):811-5 PMID: 7481773
  21. The AH-receptor: genetics, structure and function.
    Pharmacogenetics. 1993 Oct;3(5):213-30 PMID: 8287061
  22. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior.
    Science. 1994 Apr 29;264(5159):719-25 PMID: 8171325
  23. A 1.8-Mb YAC contig spanning three members of the receptor tyrosine kinase gene family (Pdgfra, Kit, and Flk1) on mouse chromosome 5.
    Genomics. 1995 Jan 20;25(2):421-32 PMID: 7540588
  24. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation.
    Science. 1995 Nov 3;270(5237):808-10 PMID: 7481772
  25. Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor.
    Mol Cell Biol. 1996 Oct;16(10):5221-31 PMID: 8816435
  26. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor.
    Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8185-9 PMID: 1325649
  27. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene.
    Science. 1992 May 1;256(5057):668-70 PMID: 1350108
  28. Cloning and expression of cDNA encoding a human ubiquitin-conjugating enzyme similar to the Drosophila bendless gene product.
    J Biochem. 1996 Sep;120(3):494-97 PMID: 8902611
  29. Negative feedback defining a circadian clock: autoregulation of the clock gene frequency.
    Science. 1994 Mar 18;263(5153):1578-84 PMID: 8128244
  30. Mouse growth-hormone-releasing hormone: precursor structure and expression in brain and placenta.
    Mol Endocrinol. 1989 Nov;3(11):1693-700 PMID: 2514346
  31. Molecular neurobiology and genetics of circadian rhythms in mammals.
    Annu Rev Neurosci. 1995;18:531-53 PMID: 7605073
  32. Forward and reverse genetic approaches to behavior in the mouse.
    Science. 1994 Jun 17;264(5166):1724-33 PMID: 8209253
  33. DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins.
    J Biol Chem. 1995 Nov 3;270(44):26292-302 PMID: 7592839
  34. Fishing for complements: finding genes by direct selection.
    Trends Genet. 1994 Oct;10(10):352-7 PMID: 7985239
  35. Temporal organization: reflections of a Darwinian clock-watcher.
    Annu Rev Physiol. 1993;55:16-54 PMID: 8466172
  36. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins.
    Science. 1989 Jul 28;245(4916):371-8 PMID: 2667136
  37. Basic local alignment search tool.
    J Mol Biol. 1990 Oct 5;215(3):403-10 PMID: 2231712
  38. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins.
    Cell. 1989 Mar 10;56(5):777-83 PMID: 2493990
  39. Messenger RNA expressed in mouse teratocarcinoma stem cells and down-regulated by a tumor-promoting phorbol ester codes for a novel transmembrane protein.
    Biochem Biophys Res Commun. 1988 Dec 15;157(2):548-57 PMID: 3202867
  40. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences.
    Hum Genet. 1992 Sep-Oct;90(1-2):41-54 PMID: 1427786
  41. Fo membrane domain of ATP synthase from bovine heart mitochondria: purification, subunit composition, and reconstitution with F1-ATPase.
    Biochemistry. 1994 Jun 28;33(25):7971-8 PMID: 8011660
  42. Temporal phosphorylation of the Drosophila period protein.
    Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2260-4 PMID: 8134384
  43. Cloning the differences between two complex genomes.
    Science. 1993 Feb 12;259(5097):946-51 PMID: 8438152
  44. Transplanted suprachiasmatic nucleus determines circadian period.
    Science. 1990 Feb 23;247(4945):975-8 PMID: 2305266
  45. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue.
    Cell. 1997 May 16;89(4):655-67 PMID: 9160756
  46. Construction of a large-insert yeast artificial chromosome library of the mouse genome.
    Mamm Genome. 1993;4(7):391-2 PMID: 8358173
  47. A circadian enhancer mediates PER-dependent mRNA cycling in Drosophila melanogaster.
    Mol Cell Biol. 1997 Jul;17(7):3687-93 PMID: 9199302
  48. Circadian timekeeping in BALB/c and C57BL/6 inbred mouse strains.
    J Neurosci. 1990 Nov;10(11):3685-94 PMID: 2230953
  49. Circadian rhythms: from gene expression to behavior.
    Curr Opin Neurobiol. 1991 Dec;1(4):556-61 PMID: 1822296
  50. Protein-protein interaction via PAS domains: role of the PAS domain in positive and negative regulation of the bHLH/PAS dioxin receptor-Arnt transcription factor complex.
    EMBO J. 1995 Jul 17;14(14):3528-39 PMID: 7628454
  51. Circadian oscillations in period gene mRNA levels are transcriptionally regulated.
    Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11711-5 PMID: 1465387
  52. DNA purification and isolation using a solid-phase.
    Nucleic Acids Res. 1994 Oct 25;22(21):4543-4 PMID: 7971285
  53. Circadian rhythms in cultured mammalian retina.
    Science. 1996 Apr 19;272(5260):419-21 PMID: 8602533
  54. A mutation of the circadian system in golden hamsters.
    Science. 1988 Sep 2;241(4870):1225-7 PMID: 3413487
  55. Constitutive overexpression of the Drosophila period protein inhibits period mRNA cycling.
    EMBO J. 1994 Aug 1;13(15):3590-8 PMID: 8062834
  56. Messenger RNA degradation in eukaryotes.
    Cell. 1993 Aug 13;74(3):413-21 PMID: 7688664
  57. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  58. Molecular genetics of Mus musculus: point mutagenesis and millimorgans.
    Genetics. 1987 May;116(1):5-8 PMID: 3596231
  59. A Drosophila circadian clock.
    Cold Spring Harb Symp Quant Biol. 1996;61:265-78 PMID: 9246455
  60. The essentials of DNA methylation.
    Cell. 1992 Jul 10;70(1):5-8 PMID: 1377983
  61. Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels.
    Nature. 1990 Feb 8;343(6258):536-40 PMID: 2105471
  62. Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system.
    Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):713-8 PMID: 9012850
  63. Neurophysiology of the suprachiasmatic circadian pacemaker in rodents.
    Physiol Rev. 1989 Jul;69(3):671-707 PMID: 2664825
  64. The Drosophila single-minded gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline development.
    Cell. 1991 Dec 20;67(6):1157-67 PMID: 1760843
  65. Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex.
    Science. 1996 Mar 22;271(5256):1740-4 PMID: 8596938
  66. Functional inactivation of genes by dominant negative mutations.
    Nature. 1987 Sep 17-23;329(6136):219-22 PMID: 2442619
Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/s0092-8674(00)80245-7
Published
1997-05-16
Pages
641-53
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3815553
Subset
IM
Grants
NIMH NIH HHS · R37 MH39592 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · T32 GM008152 · United States
NICHD NIH HHS · P30 HD28048 · United States
NIGMS NIH HHS · GM08152 · United States
Databases
GENBANK
AF000998
External Links
PubMed source DOI: 10.1016/s0092-8674(00)80245-7 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2