Reversible Block of Mouse Neural Stem Cell Differentiation in the Absence of Dicer and MicroRNAs 英文参考文献.docVIP

Reversible Block of Mouse Neural Stem Cell Differentiation in the Absence of Dicer and MicroRNAs 英文参考文献.doc

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Reversible Block of Mouse Neural Stem Cell Differentiation in the Absence of Dicer and MicroRNAs 英文参考文献

ReversibleBlockofMouseNeuralStemCell DifferentiationintheAbsenceofDicerandMicroRNAs ThereseAndersson1,2.,SabhiRahman1,2.,StephenN.Sansom1,2,JessicaM.Alsio¨1,2 ,Masahiro Kaneda1¤a,JamesSmith1,2,DonalO’Carroll3¤b,AlexanderTarakhovsky3,FrederickJ.Livesey1,2* 1Gurdon Institute, University of Cambridge, Cambridge, United Kingdom, 2Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom, 3LaboratoryofLymphocyteSignalling,TheRockefellerUniversity,NewYork,UnitedStatesofAmerica Abstract Background:ToinvestigatethefunctionsofDicerandmicroRNAsinneuralstem(NS)cellself-renewalandneurogenesis, weestablishedneuralstemcelllinesfromtheembryonicmouseDicer-nullcerebralcortex,producingneuralstemcelllines thatlackedallmicroRNAs. PrincipalFindings:Dicer-nullNScellsunderwentnormalself-renewalandcouldbemaintainedinvitroindefinitely,buthad subtlyalteredcellcyclekineticsandabnormalheterochromatinorganisation.IntheabsenceofallmicroRNAs,Dicer-nullNS cellswereincapableofgeneratingeitherglialorneuronalprogenyandexhibitedamarkeddependencyonexogenousEGF for survival. Dicer-null NS cells assumed complex differences in mRNA and protein expression under self-renewing conditions, upregulating transcripts indicative of self-renewing NS cells and expressing genes characteristic of differentiating neurons and glia. Underlining the growth-factor dependency of Dicer-null NS cells, many regulators of apoptosiswereenrichedinexpressioninthesecells.Dicer-nullNScellsinitiatesomeofthesamegeneexpressionchanges aswild-typecellsunderastrocytedifferentiatingconditions,butalsoshowaberrantexpressionoflargesetsofgenesand ultimatelyfailtocompletethedifferentiationprogramme.AcutereplacementofDicerrestoredtheirabilitytodifferentiate tobothneuronsandglia. Conclusions: The block in differentiation due to loss of Dicer and microRNAs is reversible and the significantly altered phenotypeofDicer-nullNScellsdoesnotconstituteapermanenttransformation.WeconcludethatDicerandmicroRNAs functioninthissystemtoma

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