Circadian Rhythm Generation and Tissue Specific Functions of the Clock genes

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Although clock genes are expressed in various tissues, only the suprachiasmatic nucleus (SCN) functions as the master clock governing all the bodily functions in mammals. The tissue specific functions of the clock genes were examined using clock gene mutant mice, transgenic mice as well as wild type animals. Functions of novel clock genes were also examined.1. Function of clock gene Clock and significance of the SCN tissue assemblageClock mutant mice become behaviorally arrhythmic under the continuous darkness, which has been considered due to a lack of transcription activation by mutant Clock protein. We cultured the SCN of Clock mice either in an organotypic slice or in dispersed cells on a multi-electrode dish and spontaneous firing was continuously monitored from individual SCN neurons. In homozygout Clock mice, 77% of the SCN neurons showed circadian firing rhythms in slice culture, while only 14% showed in dispersed cell culture. In wild type mice, 95 and 46% of SCN neurons showed firing rhythms, respectively. The results indicated that Clock mutation lengthened the period of individual SCN neurons but did not affects the rhythm generation, and further suggested that the intact cell assemblage with intense cell-cell communication in the intact SCN tissue is critical for the rhythm expression.2. Dec is the novel regulator of the molecular clockDEC1 and DEC2, basic helix-loop-helix (bHLH) transcription factors, repressed CLOCK/BMAL1 induced transactivation of the Per1 promoter through direct protein-protein interactions with BMAL1 and/or competition for E-box elements. DEC1 and DEC2 are expressed in the SCN in a circadian fashion with a peak in the subjective day. A brief light pulse induced DEC1 but not DEC2 expression in the SCN in a phase-dependent manner. These results indicate that DEC1 and DEC2 are novel regulators of the mammalian molecular clock.