Modeling circadian oscillations with interlocking positive and negative feedback loops.
Both positive and negative feedback loops of transcriptional regulation have been proposed to be important for the generation of circadian rhythms. To test the sufficiency of the proposed mechanisms, two differential equation-based models were constructed to describe the Neurospora crassa and Drosophila melanogaster circadian oscillators. In the model of the Neurospora oscillator, FRQ suppresses frq transcription by binding to a complex of the transcriptional activators WC-1 and WC-2, thus yielding negative feedback. FRQ also activates synthesis of WC-1, which in turn activates frq transcription, yielding positive feedback. In the model of the Drosophila oscillator, PER and TIM are represented by a "lumped" variable, "PER." PER suppresses its own transcription by binding to the transcriptional regulator dCLOCK, thus yielding negative feedback. PER also binds to dCLOCK to de-repress dclock, and dCLOCK in turn activates per transcription, yielding positive feedback. Both models displayed circadian oscillations that were robust to parameter variations and to noise and that entrained to simulated light/dark cycles. Circadian oscillations were only obtained if time delays were included to represent processes not modeled in detail (e.g., transcription and translation). In both models, oscillations were preserved when positive feedback was removed.
Smolen
P
P
Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas-Houston Medical School, Houston, Texas 77225, USA.
Baxter
D A
DA
Byrne
J H
JH
D000818:Animals; D001683:Biological Clocks / Q000502:physiology* / Q000528:radiation effects; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000502:physiology* / Q000528:radiation effects; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins; D005246:Feedback / Q000502:physiology / Q000528:radiation effects; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D019476:Insect Proteins / Q000378:metabolism; D008027:Light; D046911:Macromolecular Substances; D008954:Models, Biological; D009491:Neurospora; D009687:Nuclear Proteins / Q000378:metabolism; D056950:Period Circadian Proteins; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000502:physiology; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism
C120526:Clk protein, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C087405:FRQ protein, Neurospora crassa; D005656:Fungal Proteins; D019476:Insect Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D014157:Transcription Factors; C096445:tim protein, Drosophila; C105589:wc-1 protein, Neurospora crassa; C103772:white collar 2 protein, Neurospora; D056926:CLOCK Proteins