title: Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK.
abstract: A model of Drosophila circadian rhythm generation was developed to represent feedback loops based on transcriptional regulation of per, Clk (dclock), Pdp-1, and vri (vrille). The model postulates that histone acetylation kinetics make transcriptional activation a nonlinear function of [CLK]. Such a nonlinearity is essential to simulate robust circadian oscillations of transcription in our model and in previous models. Simulations suggest that two positive feedback loops involving Clk are not essential for oscillations, because oscillations of [PER] were preserved when Clk, vri, or Pdp-1 expression was fixed. However, eliminating positive feedback by fixing vri expression altered the oscillation period. Eliminating the negative feedback loop in which PER represses per expression abolished oscillations. Simulations of per or Clk null mutations, of per overexpression, and of vri, Clk, or Pdp-1 heterozygous null mutations altered model behavior in ways similar to experimental data. The model simulated a photic phase-response curve resembling experimental curves, and oscillations entrained to simulated light-dark cycles. Temperature compensation of oscillation period could be simulated if temperature elevation slowed PER nuclear entry or PER phosphorylation. The model makes experimental predictions, some of which could be tested in transgenic Drosophila.
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Smolen
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hardin
authors.forename: Brian S
authors.initials: BS
authors.lastname: Lo
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Baxter
authors.forename: John H
authors.initials: JH
authors.lastname: Byrne
mesh_terms: D000107:Acetylation; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000502:physiology*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006579:Heterozygote; D006657:Histones / Q000737:chemistry; D007700:Kinetics; D008027:Light; D008954:Models, Biological; D008962:Models, Theoretical; D009154:Mutation; D009991:Oscillometry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C120526:Clk protein, Drosophila; D029721:Drosophila Proteins; D006657:Histones; C109768:PDP1 protein, Drosophila; D014157:Transcription Factors; C108498:vri protein, Drosophila; D004247:DNA; D056926:CLOCK Proteins; D012321:DNA-Directed RNA Polymerases