A Drosophila Circadian Clock

The circadian clock (pacemaker, oscillator) is considered endogenous, as opposed to driven, because rhythmic oscillations persist with near 24 hour periodicity under constant conditions. It is, however, connected with the environment as the rhythm is usually entrained or synchronized by the 24 hour light-dark cycle, the major environmental zeitgeber or time cue. The clock is also connected to downstream outputs, namely, the biochemical and behavioral fluctuations that are generally observed as rhythmic phenomena. An impressive array of evidence now indicates that the per and tim genes encode bona fide components of the Drosophila melanogaster pacemaker (PER and TIM, respectively). Molecular characterization indicates that the clock mechanism includes the rhythmic accumulation and disappearance of these two gene products; protein cycling depends on transcriptional autoregulation, which is part of this intracellular clock mechanism. In this presentation, I will concentrate on recent studies from my laboratory that contribute to this Drosophila clock story. A new clock mutant predicts that there is at least one transcription factor dedicated to per and tim mRNA production. There is increasing evidence that a temporal post-transcriptional program - particularly phosphorylation of PER and TIM - also plays an important role in the time-keeping process. The characterization of the first tim mutant with an altered period phenotype reinforces the importance of the phosphorylation program. Finally, our recent experiments provide insight into the way that light entrains and phase shifts the clock. They suggest that light has a primary post-transcriptional effect on TIM, which affects its phosphorylation status as well as its half-life. This light-induced change then has secondary effects on several aspects of the clock, which leads to both phase advances and delays. These experiments underscore the fundamental role of the per-tim system in circadian time keeping and predict the existence of additional as yet unidentified clock components.

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