Graded Smad23 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells 英文参考文献.docVIP

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Graded Smad23 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells 英文参考文献.doc

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Graded Smad23 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells 英文参考文献

GradedSmad2/3ActivationIsConvertedDirectlyinto LevelsofTargetGeneExpressioninEmbryonicStem Cells MarcelaGuzman-Ayala1.,KianLeongLee1.,KonstantinosJ.Mavrakis1,ParaskeviGoggolidou2, DominicP.Norris2,VassoEpiskopou1* 1MammalianNeurogenesis,MRCClinicalSciencesCentre,ImperialCollegeSchoolofMedicine,HammersmithHospital,London,UnitedKingdom,2MammalianGenetics Unit,MRC,Harwell,UnitedKingdom Abstract TheTransformingGrowthFactor(TGF)bsignallingfamilyincludesmorphogens,suchasNodalandActivin,withimportant functionsinvertebratedevelopment.Theconcentrationofthemorphogeniscriticalforfatedecisionsintheresponding cells.Smad2andSmad3areeffectorsoftheNodal/ActivinbranchofTGFbsignalling:theyareactivatedbyreceptors,enter the nucleus and directly transcribe target genes. However, there have been no studies correlating levels of Smad2/3 activation with expression patterns of endogenous targetgenes in adevelopmental context overtime. We used mouse Embryonic Stem (ES) cells to create a system whereby levels of activated Smad2/3 can be manipulated by an inducible constitutively active receptor (Alk4*) and an inhibitor (SB-431542) that blocks specifically Smad2/3 activation. The transcriptional responses were analysed by microarrays at different time points during activation and repression. We identifiedseveralgenesthatfollowfaithfullyandreproduciblytheSmad2/3activationprofile.Twenty-sevenofthesewere novelandexpressedintheearlyembryodownstreamofSmad2/3signalling.AstheyrespondedtoSmad2/3activationin the absence of protein synthesis, they were considered direct. These immediate responsive genes included negative intracellularfeedbackfactors,likeSnoNandI-Smad7,whichinhibitthetranscriptionalactivityofSmad2/3.However,their activation did not lead to subsequent repression of target genes over time, suggesting that this type of feedback is inefficient in ES cells or it is counteracted by mechanisms such as ubiquitin-mediated degradation by Arkadia. Here we presentanEScellsystemalongwithadatabaseco