Most organisms have to cope with dramatic daily variations in their environment. In particular, light and temperature cycle robustly. Thus, light and temperature are used as synchronizing cues by circadian pacemakers, which then optimize metabolism, physiology and behavior to the time of day. The model organism Drosophila melanogaster has proved to be instrumental to understand the basic molecular and neural principles underlying circadian rhythms in animals, including humans. In fruit flies, the circadian molecular pacemaker is a transcriptional feedback loop in which PERIOD (PER) and TIMELESS (TIM) repress the dimeric CLOCK/CYCLE transactivator, and thus their own gene expression. Although temperature is a universal synchronizing cue for circadian pacemakers, how temperature cycles synchronize molecular circadian pacemakers is poorly understood. We have obtained very solid results indicating that in Drosophila, an increase in temperature triggers specifically the degradation of the pacemaker protein TIM. Interestingly, although the intracellular photoreceptor CRYPTOCHROME also targets TIM for degradation, the mechanisms underlying thermal and photic TIM degradations are completely distinct. Thermal TIM degradation is actually controlled by Calcium. With our first aim, we will therefore elucidate the role played by TIM's temperature-controlled degradation in the cell-autonomous synchronization of the circadian pacemaker with daily thermal cycles. Since Calcium plays an important role in neural communication, we will also define the role of Calcium-dependent TIM degradation in non-autonomous entrainment mechanisms in circadian neurons.
Our second aim will reveal how Calcium mediates temperature entrainment and promotes TIM degradation. Finally, our third aim will uncover how the circadian light input pathway regulates TIM`s temperature-controlled degradation, and thus how it modulates temperature inputs to the circadian pacemaker.
Our aims, combined, will provide major conceptual advances to the field of chronobiology by revealing how the Drosophila circadian molecular clock entrains to temperature cycles, and by shedding light on the complex interactions between circadian input pathways. Our work is likely to impact our understanding of circadian entrainment in mammals and humans, given the remarkable conservation of the basic mechanisms underlying circadian rhythms in animals, and the universal use of temperature as a circadian input. Circadian misalignment is associated with various ailments, such as mood disorders and metabolic diseases. Our work might thus ultimately prove helpful to understand and treat these diseases.
Circadian rhythms play a critical role in most animals: they optimize metabolism, physiology and behavior with the time of day. Because temperature is a universal environmental cue for circadian pacemakers, our goal is to uncover the molecular mechanisms underlying temperature synchronization of Drosophila circadian rhythms, and understand how light and temperature input pathways interact. Given the conservation of mechanisms underlying circadian rhythms, we anticipate that the fundamental principles revealed by our work will have long-term implication for our understanding of human circadian rhythms, and the diseases associated with their dysfunction.
