Sox9-Haploinsufficiency Causes Glucose Intolerance in Mice 英文参考文献.docVIP

Sox9-Haploinsufficiency Causes Glucose Intolerance in Mice 英文参考文献.doc

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Sox9-Haploinsufficiency Causes Glucose Intolerance in Mice 英文参考文献

Sox9-HaploinsufficiencyCausesGlucoseIntolerancein Mice ClaireL.Dubois.,HungPingShih.,PhilipA.Seymour,NishaA.Patel,JamesM.Behrmann,VictoriaNgo, MaikeSander* DepartmentofPediatricsandCellularMolecularMedicine,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract TheHMGboxtranscriptionfactorSox9playsacriticalroleinprogenitorcellexpansionduringpancreasorganogenesisand isrequiredforproperendocrinecelldevelopmentintheembryo.BasedoninvitrostudiesithasbeensuggestedthatSox9 controls expression of a network of important developmental regulators, including Tcf2/MODY5, Hnf6, and Foxa2, in pancreaticprogenitorcells.Here,wesoughtto:1)determinewhetherSox9regulatesthistranscriptionalnetworkinvivoand 2) investigate whether reduced Sox9 gene dosage leads to impaired glucose homeostasis in adult mice. Employing two geneticmodelsoftemporally-controlledSox9inactivationinpancreaticprogenitorcells,wedemonstratethatcontrarytoin vitrofindings,Sox9isnotrequiredforTcf2,Hnf6,orFoxa2expressioninvivo.Moreover,ouranalysisrevealedanovelrolefor Sox9 in maintaining the expression of Pdx1/MODY4, which is an important transcriptional regulator of beta-cell development. We further show that reduced beta-cell mass in Sox9-haploinsufficient mice leads to glucose intolerance duringadulthood.Sox9-haploinsufficientmicedisplayed50%reducedbeta-cellmassatbirth,whichrecoveredpartiallyviaa compensatory increase in beta-cell proliferation early postnatally. Endocrine islets from mice with reduced Sox9 gene dosageexhibitednormalglucosestimulatedinsulinsecretion.OurfindingsshowSox9playsanimportantroleinendocrine developmentbymaintainingNgn3andPdx1expression.GlucoseintoleranceinSox9-haploinsufficientmicesuggeststhat mutationsinSox9couldplayaroleindiabetesinhumans. Citation: DuboisCL, Shih HP,Seymour PA, Patel NA,Behrmann JM, etal.(2011) Sox9-HaploinsufficiencyCauses Glucose Intolerance inMice. PLoSONE 6(8): e23131.doi:10.1371/journal.pone.0023131 Editor:KathrinMaedler,UniversityofBremen

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