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| Item Type: | Article |
|---|---|
| Title: | Modeling feedback loops of the Mammalian circadian oscillator |
| Creators Name: | Becker-Weimann, S., Wolf, J., Herzel, H. and Kramer, A. |
| Abstract: | 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. |
| Keywords: | Physiological Adaptation, Biological Clocks, Cell Cycle Proteins, Circadian Rhythm, Computer Simulation, Cryptochromes, Feedback, Flavoproteins, Biological Models, Nuclear Proteins, Period Circadian Proteins, Signal Transduction, Transcription Factors, Transcriptional Activation, Animals, Mammals, Mice |
| Source: | Biophysical Journal |
| ISSN: | 0006-3495 |
| Publisher: | Biophysical Society |
| Volume: | 87 |
| Number: | 5 |
| Page Range: | 3023-3034 |
| Date: | November 2004 |
| Official Publication: | https://doi.org/10.1529/biophysj.104.040824 |
| PubMed: | View item in PubMed |
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