Graded NodalActivin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions 英文参考文献.docVIP

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Graded NodalActivin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions 英文参考文献.doc

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Graded NodalActivin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions 英文参考文献

GradedNodal/ActivinSignalingTitratesConversionof QuantitativePhospho-Smad2LevelsintoQualitative EmbryonicStemCellFateDecisions KianLeongLee1,2*.,SandyKeatLim2,3,4.,YuriyLvovichOrlov2,5,LeYauYit1,HenryYang6,LayTeng Ang2,LorenzPoellinger1,7,BingLim2,8 * 1CancerScienceInstituteofSingapore,NationalUniversityofSingapore,Singapore,Singapore,2GenomeInstituteofSingapore,AgencyforScience,Technology,and Research,Singapore, Singapore, 3Duke-NUS Graduate MedicalSchool, NationalUniversity ofSingapore, Singapore,Singapore, 4NUS Graduate School forIntegrative Sciences and Engineering, National University of Singapore, Singapore, Singapore, 5Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia, 6Singapore Immunology Network, Agency for Science, Technology, and Research, Singapore, Singapore, 7Department of Cell and MolecularBiology,KarolinskaInstitutet,Stockholm,Sweden, 8BethIsraelDeaconessMedicalCentre,HarvardMedicalSchool,Boston, Massachusetts,UnitedStatesof America Abstract Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisionsinadose-anddistance-dependentmanner.DuringearlyembryonicdevelopmenttheNodal/Activinpathwayis responsibleforthespecificationofmesoderm,endoderm,node,andmesendoderm.Incontradictiontothisdrivetowards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonicandepiblaststemcells.ThemolecularbasisbehindstemcellinterpretationofNodal/Activinsignalinggradients andtheundertakingofdisparatecellfatedecisionsremainspoorlyunderstood.Here,weshowthatanyperturbationof endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiationtowardsthemesendodermallineageswhilerepressionofsignalingwitht