Modelling of circadian rhythms in Drosophila incorporating the interlocked PER/TIM and VRI/PDP1 feedback loops.

Circadian rhythms of gene activity, metabolism, physiology and behaviour are observed in all the eukaryotes and some prokaryotes. In this study, we present a model to represent the transcriptional regulatory network essential for the circadian rhythmicity in Drosophila. The model incorporates the transcriptional feedback loops revealed so far in the network of the circadian clock (PER/TIM and VRI/PDP1 loops). Conventional Hill functions are not assumed to describe the regulation of genes, instead of the explicit reactions of binding and unbinding processes of transcription factors to promoters are modelled. The model simulates sustained circadian oscillations in mRNA and protein concentrations in constant darkness in agreement with experimental observations. It also simulates entrainment by light-dark cycles, disappearance of the rhythmicity in constant light and the shape of phase response curves resembling that of the experimental results. The model is robust over a wide range of parameter variations. In addition, the simulated E-box mutation, per(S) and per(L) mutants are similar to that observed in the experiments. The deficiency between the simulated mRNA levels and experimental observations in per(01), tim(01) and clk(Jrk) mutants suggests some difference on the part of the model from reality.