A model of molecular circadian clocks: Multiple mechanisms for phase shifting and a requirement for strong nonlinear interactions

A fundamental question in the field of circadian rhythms concerns Me bioche mical and molecular nature of the oscillator. There is strong evidence that circadian oscillators are cell autonomous and rely on periodic gene expres sion. In Drosophila, Neurospora, Aplysia, and vertebrates, circadian oscill ators are thought to be based on molecular autoregulatory loops composed of transcription, translation, and negative feedback by proteins on nuclear t ranscription. By studying a mathematical model of molecular clocks based on this general concept, the authors sought to determine which features such clocks must have to generate robust and stable oscillations and to allow en trainment by external stimuli such as light. The model produced circadian o scillations as an emergent property even though a time delay in protein syn thesis and rate constants of the feedback loop were much shorter than 24 h. Along with the delay in protein production, strong nonlinear interactions in macromolecular synthesis and nuclear feedback appeared to be required fo r the model to show well-behaved oscillatory behavior. Realistic phase-shif ting patterns induced by external stimuli could be achieved by multiple mec hanisms-namely, up- and downward perturbations of protein or mRNA synthesis or degradation rates. The model makes testable predictions about interacti ons between clock elements and mechanisms of entrainment and may help to un derstand the functions of the intricate molecular interactions governing ci rcadian rhythmogenesis.