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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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