Home LiteratureArticle Details
PMID: 9160756 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.

Functional identification of the mouse circadian Clock gene by transgenic BAC rescue.

Cell ·Vol. 89 ·No. 4 ·1997-05-16 ·Pages 655-67

Antoch MP, Song EJ, Chang AM, Vitaterna MH, Zhao Y, Wilsbacher LD, Sangoram AM, King DP, Pinto LH, Takahashi JS

Abstract

As a complementary approach to positional cloning, we used in vivo complementation with bacterial artificial chromosome (BAC) clones expressed in transgenic mice to identify the circadian Clock gene. A 140 kb BAC transgene completely rescued both the long period and the loss-of-rhythm phenotypes in Clock mutant mice. Analysis with overlapping BAC transgenes demonstrates that a large transcription unit spanning approximately 100,000 base pairs is the Clock gene and encodes a novel basic-helix-loop-helix-PAS domain protein. Overexpression of the Clock transgene can shorten period length beyond the wild-type range, which provides additional evidence that Clock is an integral component of the circadian pacemaking system. Taken together, these results provide a proof of principle that "cloning by rescue" is an efficient and definitive method in mice.

MeSH Terms
Animals Base Sequence CLOCK Proteins Chromosome Mapping Chromosomes, Bacterial Circadian Rhythm/genetics,physiology Cloning, Molecular DNA Primers/genetics Female Genetic Complementation Test In Situ Hybridization Male Mice Mice, Transgenic Mutation Phenotype RNA, Messenger/genetics,metabolism Trans-Activators/genetics,physiology
Chemicals
DNA Primers RNA, Messenger Trans-Activators CLOCK Proteins Clock protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Antoch M P
National Science Foundation Center for Biological Timing, Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Song E J
Chang A M
Vitaterna M H
Zhao Y
Wilsbacher L D
Sangoram A M
King D P
Pinto L H
Takahashi J S
References (49)
49 references, click to expand
  1. Genetics and molecular analysis of circadian rhythms.
    Annu Rev Genet. 1996;30:579-601 PMID: 8982466
  2. Tripping along the trail to the molecular mechanisms of biological clocks.
    Trends Neurosci. 1995 May;18(5):230-40 PMID: 7610493
  3. The Drosophila bendless gene encodes a neural protein related to ubiquitin-conjugating enzymes.
    Neuron. 1993 Aug;11(2):253-66 PMID: 8394720
  4. Positional cloning of the mouse circadian clock gene.
    Cell. 1997 May 16;89(4):641-53 PMID: 9160755
  5. Construction and characterization of a human bacterial artificial chromosome library.
    Genomics. 1996 Jun 1;34(2):213-8 PMID: 8661051
  6. A yeast artificial chromosome covering the tyrosinase gene confers copy number-dependent expression in transgenic mice.
    Nature. 1993 Mar 18;362(6417):258-61 PMID: 8459851
  7. 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
  8. 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
  9. The Neurospora clock gene frequency shares a sequence element with the Drosophila clock gene period.
    Nature. 1989 Jun 15;339(6225):558-62 PMID: 2525233
  10. A genetic map of the mouse suitable for typing intraspecific crosses.
    Genetics. 1992 Jun;131(2):423-47 PMID: 1353738
  11. Circadian rhythms in Drosophila melanogaster: analysis of period as a function of gene dosage at the per (period) locus.
    J Theor Biol. 1986 Aug 21;121(4):487-503 PMID: 3099089
  12. Restoration of circadian behavioural rhythms by gene transfer in Drosophila.
    Nature. 1984 Dec 20-1985 Jan 2;312(5996):752-4 PMID: 6440029
  13. The avian pineal, a vertebrate model system of the circadian oscillator: cellular regulation of circadian rhythms by light, second messengers, and macromolecular synthesis.
    Recent Prog Horm Res. 1989;45:279-348; discussion 348-52 PMID: 2682842
  14. P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster.
    Cell. 1984 Dec;39(2 Pt 1):369-76 PMID: 6094014
  15. Germ-line transformation involving DNA from the period locus in Drosophila melanogaster: overlapping genomic fragments that restore circadian and ultradian rhythmicity to per0 and per- mutants.
    J Neurogenet. 1986 Sep;3(5):249-91 PMID: 3097289
  16. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior.
    Science. 1994 Apr 29;264(5159):719-25 PMID: 8171325
  17. Circadian rhythms.
    Recent Prog Horm Res. 1994;49:43-90 PMID: 8146437
  18. 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
  19. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation.
    Science. 1995 Nov 3;270(5237):808-10 PMID: 7481772
  20. 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
  21. Negative feedback defining a circadian clock: autoregulation of the clock gene frequency.
    Science. 1994 Mar 18;263(5153):1578-84 PMID: 8128244
  22. Changes in abundance or structure of the per gene product can alter periodicity of the Drosophila clock.
    Nature. 1987 Mar 26-Apr 1;326(6111):390-2 PMID: 2436052
  23. Molecular neurobiology and genetics of circadian rhythms in mammals.
    Annu Rev Neurosci. 1995;18:531-53 PMID: 7605073
  24. Mouse opsin. Gene structure and molecular basis of multiple transcripts.
    J Biol Chem. 1990 Nov 25;265(33):20563-9 PMID: 1978723
  25. Genomic DNA sequencing methods.
    Methods Cell Biol. 1995;48:551-69 PMID: 8531742
  26. Temporal organization: reflections of a Darwinian clock-watcher.
    Annu Rev Physiol. 1993;55:16-54 PMID: 8466172
  27. The analysis of new short-period circadian rhythm mutants suggests features of D. melanogaster period gene function.
    J Neurogenet. 1992 May;8(2):101-13 PMID: 1634995
  28. Circadian clock phenotypes of chromosome aberrations with a breakpoint at the per locus.
    Mol Gen Genet. 1981;183(2):243-51 PMID: 6799743
  29. 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
  30. Transplanted suprachiasmatic nucleus determines circadian period.
    Science. 1990 Feb 23;247(4945):975-8 PMID: 2305266
  31. p53 function and dysfunction.
    Cell. 1992 Aug 21;70(4):523-6 PMID: 1505019
  32. Entrainment pathways and the functional organization of the circadian system.
    Prog Brain Res. 1996;111:103-19 PMID: 8990910
  33. A promoterless period gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the Drosophila nervous system.
    Neuron. 1994 Mar;12(3):555-70 PMID: 8155319
  34. Molecular approaches to understanding circadian oscillations.
    Annu Rev Physiol. 1993;55:729-53 PMID: 8466190
  35. The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression.
    Neuron. 1997 May;18(5):711-22 PMID: 9182797
  36. 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
  37. Tumor suppressor genes.
    Bioessays. 1990 Feb;12(2):60-6 PMID: 2140509
  38. Circadian rhythms in cultured mammalian retina.
    Science. 1996 Apr 19;272(5260):419-21 PMID: 8602533
  39. Constitutive overexpression of the Drosophila period protein inhibits period mRNA cycling.
    EMBO J. 1994 Aug 1;13(15):3590-8 PMID: 8062834
  40. Production of transgenic mice with yeast artificial chromosomes.
    Trends Genet. 1997 Feb;13(2):61-6 PMID: 9055607
  41. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  42. Molecular genetics of Mus musculus: point mutagenesis and millimorgans.
    Genetics. 1987 May;116(1):5-8 PMID: 3596231
  43. A Drosophila circadian clock.
    Cold Spring Harb Symp Quant Biol. 1996;61:265-78 PMID: 9246455
  44. The essentials of DNA methylation.
    Cell. 1992 Jul 10;70(1):5-8 PMID: 1377983
  45. 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
  46. Construction of a panel of transgenic mice containing a contiguous 2-Mb set of YAC/P1 clones from human chromosome 21q22.2.
    Genomics. 1995 Jun 10;27(3):425-34 PMID: 7558023
  47. Neurophysiology of the suprachiasmatic circadian pacemaker in rodents.
    Physiol Rev. 1989 Jul;69(3):671-707 PMID: 2664825
  48. Biological clocks in the retina: cellular mechanisms of biological timekeeping.
    Int Rev Cytol. 1993;146:83-144 PMID: 8360015
  49. Genetic analysis of circadian clocks.
    Annu Rev Physiol. 1993;55:683-728 PMID: 8466189
Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/s0092-8674(00)80246-9
Published
1997-05-16
Pages
655-67
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3764491
Subset
IM
Grants
NIMH NIH HHS · R37 MH39592 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · T32 GM08152 · United States
NIGMS NIH HHS · T32 GM008152 · United States
NICHD NIH HHS · P30 HD28048 · United States
Databases
GENBANK
AF000998
External Links
PubMed source DOI: 10.1016/s0092-8674(00)80246-9 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