PERIOD–TIMELESS Interval Timer May Require an Additional Feedback Loop

In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms. This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon. The possible mechanisms underlying the cytoplasmic “interval timer” created by PERIOD–TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure. Incorporation of this additional feedback into a full circadian model produced results that are consistent with previous experimental observations of wild-type protein profiles and numerous mutant phenotypes.: The ability of an organism to adapt to daily changes in the environment, via a circadian clock, is an inherently interesting phenomenon recently connected to several human health issues. Decades of experiments on one of the smallest model animals, the fruit fly Drosophila, has illustrated significant similarities with the mammal circadian system. Within Drosophila, the PERIOD and TIMELESS proteins are central to controlling this rhythmicity and were recently shown to have a rapid and stable association creating an “interval” timer in the cell's cytoplasm. This interval timer creates the necessary delay between the expression and activity of these genes, and is directly opposed to the previous hypothesis of a delay created by slow association. We use several mathematical models to investigate the unknown factors controlling this timer. Using a novel positive feedback loop, we construct a circadian model consistent with the interval timer and many wild-type and mutant experimental observations. Our results suggest several novel genes and interactions to be tested experimentally.