title: Toward a detailed computational model for the mammalian circadian clock.
abstract: We present a computational model for the mammalian circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, Clock, and Rev-Erb alpha genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erbalpha and Bmal1 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in humans, such as advanced or delayed sleep phase syndrome, whereas the lack of entrainment by light-dark cycles can be related to the non-24h sleep-wake syndrome. The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of Bmal1 expression.
authors.affiliation: Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, C. P. 231, B-1050 Brussels, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leloup
authors.forename: Albert
authors.initials: A
authors.lastname: Goldbeter
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D003624:Darkness; D029721:Drosophila Proteins; D005136:Eye Proteins; D005246:Feedback; D005420:Flavoproteins / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D008322:Mammals / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D015233:Models, Statistical; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; D017440:Photoperiod; D017956:Photoreceptor Cells, Invertebrate; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C064353:NR1D1 protein, human; C539022:PER1 protein, human; C119828:cry protein, Drosophila; C538943:CLOCK protein, human