Modeling the molecular regulatory mechanism of circadian rhythms in Drosophila

Thanks to genetic and biochemical advances on the molecular mechanism of ci rcadian rhythms in Drosophila, theoretical models closely related to experi mental observations can be considered for the regulatory mechanism of the c ircadian clock in this organism. Modeling is based on the autoregulatory ne gative feedback exerted by a complex between PER and TIM proteins on the ex pression of per and tim genes. The model predicts the occurrence of sustain ed circadian oscillations in continuous darkness. When incorporating light- induced TIM degradation, the model accounts for damping of oscillations in constant light, entrainment of the rhythm by light-dark cycles of varying p eriod or photoperiod, and phase shifting by light pulses. The model further provides a molecular dynamical explanation for the permanent or transient suppression of circadian rhythmicity triggered in a variety of organisms by a critical pulse of light. Finally, the model shows that to produce a robu st rhythm the various clock genes must be expressed at the appropriate leve ls since sustained oscillations only occur in a precise range of parameter values. (C) 2000 John Wiley & Sons, Inc.