Modeling feedback loops of the Mammalian circadian oscillator.
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-erbalpha-/- 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- erbalpha -/- mutant mice.
Becker-Weimann
Sabine
S
Institute for Theoretical Biology, and Laboratory of Chronobiology--Institute of Medical Immunology (Charité), Humboldt-University Berlin, 10115 Berlin, Germany.
Wolf
Jana
J
Herzel
Hanspeter
H
Kramer
Achim
A
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D003198:Computer Simulation; D056931:Cryptochromes; D005246:Feedback / Q000502:physiology*; D005420:Flavoproteins / Q000378:metabolism*; D008322:Mammals; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D056950:Period Circadian Proteins; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000502:physiology
D018797:Cell Cycle Proteins; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D005420:Flavoproteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors