Circadian rhythms are the daily biological and physiological processes that cycle with a period of about 24 hours. In recent years, the circadian field has progressed significantly from the discovery of many genes involved in the core circadian function. The first mammalian circadian gene that was cloned, Clock, was shown to be a transcription factor that is critical for the proper functioning of the circadian system in mammals. Many studies have been conducted with the Clock Δ19 mutation and how ubiquitous perturbations in Clock gene function affect the circadian system at both the behavioral and molecular levels. However, the tissue specific role of the Clock gene in controlling circadian rhythms has not been addressed. In addition, circadian studies have not been conducted with a mouse model that contains a loss of expression of the Clock gene. In this study, we have attempted to address these two issues using a variety of different methods. First, we utilized the tetracycline transactivator system and showed that expression of wild-type Clock and mutant Clock Δ19 transgenes in the SCN/brain is sufficient to alter circadian locomotor behavior in darkness. Second, we created Clock gene knockout mice from ES cells containing a genetrap in the Clock locus in order to determine the absence of Clock gene expression on circadian locomotor behavior and the circadian molecular machinery. From these set of experiments, we have found that the loss of Clock expression does not severely attenuate the expression levels and oscillations of the core circadian transcripts. As a result, the circadian free running period and wheel running rhythmicity of Clock knockout mice are not severely compromised as it is in Clock Δ19 mutant mice. Third, we investigated the light resetting properties of the circadian system in the absence of Clock gene expression. From these experiments, we found that the light resetting properties were significantly altered in Clock knockout mice compared to wild-type mice and were altered in a manner that was significantly different from that of ClockΔ19 mutant mice at both the behavioral and molecular levels. The results from this study implicate the importance of proper Clock function and gene expression in the light resetting of the circadian Clock.
|Advisor:||Takahashi, Joseph S.|
|Commitee:||Allada, Ravi, Woodruff, Teresa|
|Department:||Interdepartmental Biological Sciences Program|
|School Location:||United States -- Illinois|
|Source:||DAI-B 70/05, Dissertation Abstracts International|
|Keywords:||Circadian rhythms, Clock, Genetrap, Sleep, Tetracycline transactivator system|
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