Abstract
Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK) and CYCLE (CYC) initiates the circadian system by promoting rhythmic transcription of hundreds of genes. However, it is still not clear whether high amplitude transcriptional oscillations are essential for circadian timekeeping. In order to address this issue, we generated flies in which the amplitude of CLK-driven transcription can be reduced partially (approx. 60%) or strongly (90%) without affecting the average levels of CLK-target genes. The impaired transcriptional oscillations lead to low amplitude protein oscillations that were not sufficient to drive outputs of peripheral oscillators. However, circadian rhythms in locomotor activity were resistant to partial reduction in transcriptional and protein oscillations. We found that the resilience of the brain oscillator is depending on the neuronal communication among circadian neurons in the brain. Indeed, the capacity of the brain oscillator to overcome low amplitude transcriptional oscillations depends on the action of the neuropeptide PDF and on the pdf-expressing cells having equal or higher amplitude of molecular rhythms than the rest of the circadian neuronal groups in the fly brain. Therefore, our work reveals the importance of high amplitude transcriptional oscillations for cell-autonomous circadian timekeeping. Moreover, we demonstrate that the circadian neuronal network is an essential buffering system that protects against changes in circadian transcription in the brain.
Highlights
Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes
The current model states that circadian clocks keep time by the use of biochemical feedback loops
We found that a decrease of more than 50% in the amplitude of circadian oscillations leads to impaired function of circadian physiological outputs in the periphery but does not significantly affect circadian behavior
Summary
Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster, the master genes Clock (Clk) and cycle (cyc) activate the circadian system by promoting rhythmic transcription of several key genes. Three of these target gene products, PERIOD (PER) [3], TIMELESS (TIM) [4], and CWO [5,6,7] repress CLK-CYC mediated transcription on a daily basis. A central role for transcriptional feedback loops has been challenged by the idea that other modes of regulation, like phosphorylation of key clock proteins as PER are more important for circadian timekeeping. Other work has re-confirmed the importance of transcriptional regulation for timekeeping in Drosophila and mammals [13,14,15]
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