sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development 英文参考文献.docVIP

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sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development 英文参考文献.doc

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sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development 英文参考文献

sox9bIsaKeyRegulatorofPancreaticobiliaryDuctal SystemDevelopment MarionDelous1.*,ChunyueYin1.,DonghunShin1¤,NikolayNinov1,JulianaDebritoCarten2,3, LuyuanPan4,TaylurP.Ma4,StevenA.Farber2,3,CeciliaB.Moens4,DidierY.R.Stainier1* 1DepartmentofBiochemistryandBiophysics,PrograminDevelopmentalandStemCellBiology,LiverCenterandDiabetesCenter,UniversityofCaliforniaSanFrancisco, SanFrancisco,California,UnitedStatesofAmerica,2DepartmentofBiology,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica,3Departmentof Embryology,TheCarnegieInstitutionforScience,Baltimore,Maryland,UnitedStatesofAmerica,4HowardHughesMedicalInstituteandDivisionofBasicScience,Fred HutchinsonCancerResearchCenter,Seattle,Washington,UnitedStatesofAmerica Abstract The pancreaticobiliary ductal system connects the liver and pancreas to the intestine. It is composed of the hepatopancreatic ductal (HPD) system as well as the intrahepatic biliary ducts and the intrapancreatic ducts. Despite its physiologicalimportance,thedevelopmentofthepancreaticobiliaryductalsystemremainspoorlyunderstood.TheSRY- relatedtranscriptionfactorSOX9isexpressedinthemammalianpancreaticobiliaryductalsystem,buttheperinatallethality ofSox9heterozygousmicemakesloss-of-functionanalyseschallenging.Weturnedtothezebrafishtoassesstheroleof SOX9 in pancreaticobiliary ductal system development. We first show that zebrafish sox9b recapitulates the expression patternofmouseSox9inthepancreaticobiliaryductalsystemanduseanonsensealleleofsox9b,sox9bfh313,todissectits functioninthemorphogenesisofthisstructure.Strikingly,sox9bfh313homozygousmutantssurvivetoadulthoodandexhibit cholestasis associated with hepatic and pancreatic duct proliferation, cyst formation, and fibrosis. Analysis of sox9bfh313 mutantembryosandlarvaerevealsthattheHPDcellsappeartomis-differentiatetowardshepaticand/orpancreaticfates, resultinginadysmorphicstructure.Theintrahepaticbiliarycellsarespecifiedbutfailtoassembleintoafunctionalnetwork. Similarly, intrapancreatic duc