Gene Dosage Effects of the Imprinted Delta-Like Homologue 1 (Dlk1Pref1) in Development Implications for the Evolution of Imprinting 英文参考文献.docVIP

GeneDosageEffectsoftheImprintedDelta-Like Homologue1(Dlk1/Pref1)inDevelopment:Implications fortheEvolutionofImprinting SimaoTeixeiradaRocha1,MarikaCharalambous1,Shau-PingLin2,IsabelGutteridge1,YokoIto1 ,Dionne Gray1,WendyDean3,AnneC.Ferguson-Smith1* 1DepartmentofPhysiology,DevelopmentandNeuroscience,UniversityofCambridge,Cambridge,UnitedKingdom,2InstituteofBiotechnology,CollegeofBioresources andAgriculture,NationalTaiwanUniversity,Taipei,Taiwan,3DevelopmentalGeneticsandImprintingLaboratory,TheBabrahamInstitute,Cambridge,UnitedKingdom Abstract Genomic imprinting is a normal process that causes genes to be expressed according to parental origin. The selective advantageconferredbyimprintingisnotunderstoodbutishypothesisedtoactondosage-criticalgenes.Here,wereporta unique model in which the consequences of a single, double, and triple dosage of the imprinted Dlk1/Pref1 , normally repressed on the maternally inherited chromosome, can be assessed in the growing embryo. BAC-transgenic mice were generated that over-express Dlk1 from endogenous regulators at all sites of embryonic activity. Triple dosage causes lethality associated with major organ abnormalities. Embryos expressing a double dose of Dlk1, recapitulating loss of imprinting, are growth enhanced but fail to thrive in early life, despite the early growth advantage. Thus, any benefit conferred by increased embryonic size is offset by postnatal lethality. We propose a negative correlation between gene dosageandsurvivalthatfixesanupperlimitongrowthpromotionbyDlk1,andwehypothesizethattrade-offbetween growthandlethalitymighthavedrivenimprintingatthislocus. Citation:TeixeiradaRochaS,CharalambousM,LinS-P,GutteridgeI,ItoY,etal.(2009)GeneDosageEffectsoftheImprintedDelta-LikeHomologue1(Dlk1/Pref1) inDevelopment:ImplicationsfortheEvolutionofImprinting.PLoSGenet5(2):e1000392.doi:10.1371/journal.pgen.1000392 Editor:WolfReik,TheBabrahamInstitute,UnitedKingdom ReceivedDecember9,2008;AcceptedJanuary26,2009;PublishedFebruary27,2