Disruption of Hepatic Leptin Signaling Protects Mice From Age- and Diet-Related Glucose Intolerance

Our computational model of the circadian clock comprised the feedback loop between LATE ELONGATED HYPOCOTYL (LHY), CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and TIMING OF CAB EXPRESSION 1 (TOC1), and a predicted, interlocking feedback loop involving TOC1 and a hypothetical component Y. Experiments based on model predictions suggested GIGANTEA (GI) as a candidate for Y. We now extend the model to include a recently demonstrated feedback loop between the TOC1 homologues PSEUDO‐RESPONSE REGULATOR 7 (PRR7), PRR9 and LHY and CCA1. This three‐loop network explains the rhythmic phenotype of toc1 mutant alleles. Model predictions fit closely to new data on the gi;lhy;cca1 mutant, which confirm that GI is a major contributor to Y function. Analysis of the three‐loop network suggests that the plant clock consists of morning and evening oscillators, coupled intracellularly, which may be analogous to coupled, morning and evening clock cells in Drosophila and the mouse.

[1]  D. E. Somers,et al.  Control of circadian rhythms and photoperiodic flowering by the Arabidopsis GIGANTEA gene. , 1999, Science.

[2]  A. Hall,et al.  Distinct regulation of CAB and PHYB gene expression by similar circadian clocks. , 2002, The Plant journal : for cell and molecular biology.

[3]  S. Tabata,et al.  Comparative genetic studies on the APRR5 and APRR7 genes belonging to the APRR1/TOC1 quintet implicated in circadian rhythm, control of flowering time, and early photomorphogenesis. , 2003, Plant & cell physiology.

[4]  Lawrence F. Shampine,et al.  The MATLAB ODE Suite , 1997, SIAM J. Sci. Comput..

[5]  D. E. Somers,et al.  Targeted degradation of TOC1 by ZTL modulates circadian function in Arabidopsis thaliana , 2003, Nature.

[6]  M. Sussman,et al.  T-DNA as an Insertional Mutagen in Arabidopsis , 1999, Plant Cell.

[7]  I. N. Karatsoreos,et al.  Chronobiology: biological timekeeping , 2004, Physiology & Behavior.

[8]  David Alabadí,et al.  Dual Role of TOC1 in the Control of Circadian and Photomorphogenic Responses in Arabidopsis Online version contains Web-only data. Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.006734. , 2003, The Plant Cell Online.

[9]  Anthony Hall,et al.  The Molecular Basis of Temperature Compensation in the Arabidopsis Circadian Clock[W] , 2006, The Plant Cell Online.

[10]  D A Rand,et al.  Design principles underlying circadian clocks , 2004, Journal of The Royal Society Interface.

[11]  P. Quail,et al.  Arabidopsis PSEUDO-RESPONSE REGULATOR7 Is a Signaling Intermediate in Phytochrome-Regulated Seedling Deetiolation and Phasing of the Circadian Clock Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.015065. , 2003, The Plant Cell Online.

[12]  A. Goldbeter,et al.  A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins , 1998, Journal of biological rhythms.

[13]  Stacey L. Harmer,et al.  Critical Role for CCA1 and LHY in Maintaining Circadian Rhythmicity in Arabidopsis , 2002, Current Biology.

[14]  Daniel B. Forger,et al.  A detailed predictive model of the mammalian circadian clock , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Paul E. Brown,et al.  Extension of a genetic network model by iterative experimentation and mathematical analysis , 2005, Molecular systems biology.

[16]  C Robertson McClung,et al.  Two Arabidopsis circadian oscillators can be distinguished by differential temperature sensitivity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  C Robertson McClung,et al.  PSEUDO-RESPONSE REGULATOR 7 and 9 Are Partially Redundant Genes Essential for the Temperature Responsiveness of the Arabidopsis Circadian Clock , 2005, The Plant Cell Online.

[18]  D. E. Somers,et al.  Cloning of the Arabidopsis clock gene TOC1, an autoregulatory response regulator homolog. , 2000, Science.

[19]  P. Hardin,et al.  Interlocked feedback loops within the Drosophila circadian oscillator. , 1999, Science.

[20]  J Chory,et al.  The regulation of circadian period by phototransduction pathways in Arabidopsis , 1995, Science.

[21]  Serge Daan,et al.  A functional analysis of circadian pacemakers in nocturnal rodents , 1976, Journal of comparative physiology.

[22]  Peter Ruoff,et al.  The Temperature-Compensated Goodwin Model Simulates Many Circadian Clock Properties , 1996 .

[23]  C. Robertson McClung,et al.  Plant Circadian Rhythms , 2006, The Plant Cell Online.

[24]  Serge Daan,et al.  A functional analysis of circadian pacemakers in nocturnal rodents , 1976, Journal of comparative physiology.

[25]  Francis J Doyle,et al.  A novel computational model of the circadian clock in Arabidopsis that incorporates PRR7 and PRR9 , 2006, Molecular systems biology.

[26]  S. Kay,et al.  Quantitative Analysis of Drosophila period Gene Transcription in Living Animals , 1997, Journal of biological rhythms.

[27]  S. Kay,et al.  A Role for LKP2 in the Circadian Clock of Arabidopsis Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.010332. , 2001, The Plant Cell Online.

[28]  Andrew J. Millar,et al.  The ELF4 gene controls circadian rhythms and flowering time in Arabidopsis thaliana , 2002, Nature.

[29]  Anthony Hall,et al.  The TIME FOR COFFEE Gene Maintains the Amplitude and Timing of Arabidopsis Circadian Clocks Online version contains Web-only data. Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.013730. , 2003, The Plant Cell Online.

[30]  Takeshi Mizuno,et al.  PSEUDO-RESPONSE REGULATORS, PRR9, PRR7 and PRR5, together play essential roles close to the circadian clock of Arabidopsis thaliana. , 2005, Plant & cell physiology.

[31]  S. Tabata,et al.  Characterization of the APRR9 pseudo-response regulator belonging to the APRR1/TOC1 quintet in Arabidopsis thaliana. , 2003, Plant & cell physiology.

[32]  E. Huq,et al.  Direct targeting of light signals to a promoter element-bound transcription factor. , 2000, Science.

[33]  M S Turner,et al.  Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana. , 2005, Journal of theoretical biology.

[34]  Stacey L. Harmer,et al.  Overlapping and Distinct Roles of PRR7 and PRR9 in the Arabidopsis Circadian Clock , 2005, Current Biology.

[35]  I. Carré,et al.  Light‐regulated translation mediates gated induction of the Arabidopsis clock protein LHY , 2003, The EMBO journal.

[36]  A. Hall,et al.  Functional independence of circadian clocks that regulate plant gene expression , 2000, Current Biology.

[37]  D. E. Somers,et al.  Forward Genetic Analysis of the Circadian Clock Separates the Multiple Functions of ZEITLUPE1[W] , 2006, Plant Physiology.

[38]  Steve A. Kay,et al.  Reciprocal Regulation Between TOC1 and LHY/CCA1 Within the Arabidopsis Circadian Clock , 2001, Science.

[39]  Zhi-Yong Wang,et al.  Constitutive Expression of the CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) Gene Disrupts Circadian Rhythms and Suppresses Its Own Expression , 1998, Cell.

[40]  José Agosto,et al.  Coupled oscillators control morning and evening locomotor behaviour of Drosophila , 2004, Nature.

[41]  G. Coupland,et al.  GIGANTEA: a circadian clock‐controlled gene that regulates photoperiodic flowering in Arabidopsis and encodes a protein with several possible membrane‐spanning domains , 1999, The EMBO journal.

[42]  William J. Schwartz,et al.  Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro , 2000, Nature Neuroscience.

[43]  A. Samach,et al.  Novel roles for GIGANTEA revealed under environmental conditions that modify its expression in Arabidopsis and Medicago truncatula , 2006, Planta.

[44]  G. E. Duffield,et al.  DNA Microarray Analyses of Circadian Timing: The Genomic Basis of Biological Time , 2003, Journal of neuroendocrinology.

[45]  T. Mizuno,et al.  Light response of the circadian waves of the APRR1/TOC1 quintet: when does the quintet start singing rhythmically in Arabidopsis? , 2001, Plant & cell physiology.

[46]  J. Putterill,et al.  T-DNA tagging of a flowering-time gene and improved gene transfer by in planta transformation of Arabidopsis , 1998 .

[47]  G. Coupland,et al.  Distinct Roles of GIGANTEA in Promoting Flowering and Regulating Circadian Rhythms in Arabidopsis , 2005, The Plant Cell Online.

[48]  S. Kay,et al.  Positive and Negative Factors Confer Phase-Specific Circadian Regulation of Transcription in Arabidopsisw⃞ , 2005, The Plant Cell Online.