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Modeling Feedback Loops of the Mammalian Circadian Oscillator

2004; Elsevier BV; Volume: 87; Issue: 5 Linguagem: Inglês

10.1529/biophysj.104.040824

1542-0086

Sabine Becker-Weimann, Jana Wolf, Hanspeter Herzel, Achim Kramer,

Spaceflight effects on biology

The suprachiasmatic nucleus governs daily variations of physiology and behavior in mammals. Within single neurons, interlocked transcriptional/translational feedback loops generate circadian rhythms on the molecular level. We present a mathematical model that reflects the essential features of the mammalian circadian oscillator to characterize the differential roles of negative and positive feedback loops. The oscillations that are obtained have a 24-h period and are robust toward parameter variations even when the positive feedback is replaced by a constantly expressed activator. This demonstrates the crucial role of the negative feedback for rhythm generation. Moreover, it explains the rhythmic phenotype of Rev-erbα−/− mutant mice, where a positive feedback is missing. The interplay of negative and positive feedback reveals a complex dynamics. In particular, the model explains the unexpected rescue of circadian oscillations in Per2Brdm1/Cry2−/− double-mutant mice (Per2Brdm1 single-mutant mice are arrhythmic). Here, a decrease of positive feedback strength associated with mutating the Per2 gene is compensated by the Cry2−/− mutation that simultaneously decreases the negative feedback strength. Finally, this model leads us to a testable prediction of a molecular and behavioral phenotype: circadian oscillations should be rescued when arrhythmic Per2Brdm1 mutant mice are crossed with Rev- erbα−/− mutant mice.