Circadian Clock in Drosophila
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Circadian Clock in Drosophila
Circadian rhythms are near-24-hour rhythms of biological processes that persist in the absence of environmental cues such as light and temperature. Such rhythms have been described in organisms ranging from photosynthetic prokaryotes to higher eukaryotes and reflect the existence of an underlying intrinsic circadian oscillator or biological clock. This circadian oscillator may impart an advantage to the organism by temporally orchestrating physiological and behavioral processes to better adapt to the predictable daily changes in the environment. For example, in Cyanobacteria and Arabidopsis, the circadian oscillator directs transcription of the photosynthetic machinery to the daylight hours, thereby ensuring efficient assimilation of light energy. In mammals, circadian consolidation of locomotor activity to time of food availability and predator avoidance functions to improve survival (Ref.1). The best-known rhythms are those that display an approximate 24-hour period length, entrainment of the clock in response to light-dark transitions and a temperature compensation of the period. Circadian rhythms contain at least three elements: a) input pathways that relay environmental information to a circadian pacemaker (clock) b) the circadian pacemaker that generates the oscillation and c) output pathway(s) through which the pacemaker regulates various output rhythms (Ref.2).

In Drosophila, five genes have been identified that are necessary for circadian feedback loop function: Per (Period), Tim (Timeless), dClk (Drosophila Clock), Cyc (Cycle), and Dbt (Double-time, closely related to human CSNK-I-Epsilon). Three of these genes-Per, Tim, and dClk-are rhythmically expressed: Per and Tim mRNA levels peak early in the evening, and dClk mRNA levels peak late at night to early in the morning (Ref.4). Activation of Per and Tim transcription is mediated by two basic helix-loop-helix PAS-domain transcription factors, dClk and Cyc, which form heterodimers that target CACGTG E-box enhancers in the Per and Tim promoters. Per and Tim proteins slowly accumulate as heterodimers and feedback to inhibit dClk-Cyc dependent transcription. Vri accumulates quickly and inhibits dClk transcription, then the slower accumulating levels of Pdp1Epsilon (PAR domain protein-1) activate dClk transcription. Although Per and Tim mRNAs reach peak levels early in the evening, Per and Tim levels do not peak until late evening. This delay results from the initial destabilization of Per by Dbt-dependent phosphorylation, followed by the stabilization of Per by dimerization with Tim. Per-Tim dimmers then move into the nucleus and sequester dClk-Cyc dimmers. This interaction effectively inhibits dClk-Cyc function, which leads to the repression of Per and Tim transcription and the derepression of dClk transcription. As Per-Tim levels fall early in the morning, dClk-Cyc dimmers are released and repress dClk expression, thereby decreasing dClk mRNA levels so that they are low by the end of the day. Concomitant with the drop in dClk mRNA levels (through dClk-Cyc-dependent repression) is the accumulation of Per, Tim and other Ccg (Clock Controlled Gene) mRNA (through E-box-dependent dClk-Cyc activation). As dClk mRNA falls to low levels early in the evening, the levels of dClk-Cyc also fall, leading to a decrease in Per and Tim transcription and an increase in dClk mRNA accumulation. A new cycle then begins as high levels of Per and Tim enter the nucleus and dClk starts to accumulate late at night (Ref.4). The gene product of the cryptochrome gene, Cry serves two roles, in the central oscillator it serves, as the predominant photoreceptor but is dispensable within the core clockwork and in peripheral oscillators, however, Cry serves as an integral clock component and facilitate Per-Tim nuclear translocation, or vice versa.

Several inroads have been made in the enigmatic phenomenon of circadian rhythms. As studies of circadian oscillators are rapidly progressing several important features are becoming clear. Central and peripheral oscillator mechanisms are different in flies. The small ventral lateral neurons do not require Cry for oscillator function, whereas peripheral oscillators do (Ref.5). Thus, even between species as closely related as flies and moths, the central oscillator has acquired species-specific differences.