Quantitative Analysis of Phase Wave of Gene Expression in the Mammalian Central Circadian Clock Network 英文参考文献.docVIP

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Quantitative Analysis of Phase Wave of Gene Expression in the Mammalian Central Circadian Clock Network 英文参考文献.doc

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Quantitative Analysis of Phase Wave of Gene Expression in the Mammalian Central Circadian Clock Network 英文参考文献

QuantitativeAnalysisofPhaseWaveofGeneExpression intheMammalianCentralCircadianClockNetwork HirokazuFukuda1,2,IsaoTokuda3,SeiichiHashimoto4¤,NaotoHayasaka5* 1Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan, 2PRESTO, Japan Science and TechnologyAgency(JST),Kawaguchi,Saitama,Japan,3DepartmentofMicroSystemTechnology,RitsumeikanUniversity,Shiga,Japan,4MolecularMedicineResearch Labs,DrugDiscoveryResearch,AstellasPharmaInc.,Tsukuba,Ibaraki,Japan,5DepartmentofAnatomyandNeurobiology,KinkiUniversitySchoolofMedicine,Osaka- Sayama,Osaka,Japan Abstract Background: The suprachiasmatic nucleus (SCN), the master circadian clock, is a heterogeneous oscillator network, yet displays a robust synchronization dynamics. Recent single-cell bioluminescent imaging revealed temporal gradients in circadianclockgeneexpressionintheSCNexvivo.However,duetotechnicaldifficultyinbiologicalapproachestoelucidate theentirenetworkstructureoftheSCN,characteristicsofthegradient,whichwerefertoasphasewave,remainunknown. Methodology/Principal Findings: We implemented new approaches, i.e., quantitative analysis and model simulation to characterizethephasewavesinPer2::LuciferaseclockreportergeneexpressionoftheratSCNslice.Ourquantitativestudy demonstratednotonlyahighdegreeofsynchronizationbetweentheneuronsandregularoccurrenceofthephasewave propagation,butalsoasignificantamountofphasefluctuationscontainedinthewave.Inaddition,oursimulationsbased onlocalcouplingmodelsuggestthattheintercellularcouplingstrengthestimatedbythemodelsimulationsissignificantly higherthanthecriticalvalueforgeneratingthephasewaves.ModelsimulationsalsosuggestthatheterogeneityoftheSCN neurons is one of the main factors causing the phase wave fluctuations. Furthermore, robustness of the SCN network againstdynamicalnoiseandvariationofthenaturalfrequenciesinherentintheseneuronswasquantitativelyassessed. Conclusions/Significance: To our knowledge, this is the fi