Abstract
The circadian clock mechanism in the mouse is composed of interlocking transcriptional feedback loops. Two transcription factors, CLOCK and BMAL1, are believed to be essential components of the circadian clock. We have used the Cre-LoxP system to generate whole-animal knockouts of CLOCK and evaluated the resultant circadian phenotypes. Surprisingly, CLOCK-deficient mice continue to express robust circadian rhythms in locomotor activity, although they do have altered responses to light. At the molecular and biochemical levels, clock gene mRNA and protein levels in both the master clock in the suprachiasmatic nuclei and a peripheral clock in the liver show alterations in the CLOCK-deficient animals, although the molecular feedback loops continue to function. Our data challenge a central feature of the current mammalian circadian clock model regarding the necessity of CLOCK:BMAL1 heterodimers for clock function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Biological Clocks / genetics*
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Biological Clocks / radiation effects
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CLOCK Proteins
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Circadian Rhythm / genetics*
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Circadian Rhythm / radiation effects
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Dimerization
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Feedback, Physiological / genetics
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Light
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Liver / cytology
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Motor Activity / drug effects
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Motor Activity / genetics
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Phenotype
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Photic Stimulation
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RNA, Messenger / metabolism
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Suprachiasmatic Nucleus / cytology
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Suprachiasmatic Nucleus / metabolism*
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Trans-Activators / genetics*
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Trans-Activators / metabolism*
Substances
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ARNTL Transcription Factors
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Bmal1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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RNA, Messenger
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Trans-Activators
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CLOCK Proteins
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Clock protein, mouse