A Heart-Hand Syndrome Gene Tfap2b Plays a Critical Role in the Development and Remodeling of Mouse Ductus Arteriosus and Limb Patterning 英文参考文献.docVIP

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A Heart-Hand Syndrome Gene Tfap2b Plays a Critical Role in the Development and Remodeling of Mouse Ductus Arteriosus and Limb Patterning 英文参考文献.doc

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A Heart-Hand Syndrome Gene Tfap2b Plays a Critical Role in the Development and Remodeling of Mouse Ductus Arteriosus and Limb Patterning 英文参考文献

AHeart-HandSyndromeGene:Tfap2bPlaysaCritical RoleintheDevelopmentandRemodelingofMouse DuctusArteriosusandLimbPatterning FengZhao1*¤,Anja-KatrinBosserhoff2,ReinhardBuettner3,MarkusMoser4 1DepartmentofPediatrics,MountSinaiSchoolofMedicine,NewYork,NewYork,UnitedStatesofAmerica,2InstituteofPathology,MolecularPathology,Universityof Regensburg, Regensburg, Germany, 3Institute of Pathology, University Hospital Cologne, Cologne, Germany, 4Max-Planck-Institute of Biochemistry, Martinsried, Germany Abstract Background:Patentductusarteriosus(PDA)isoneofthemostcommonformsofcongenitalheartdisease.Mutationsin transcriptionfactorTFAP2BcauseCharsyndrome,ahumandisordercharacterizedbyPDA,facialdysmorphysmandhand anomalies. Animal research data are needed to understand the mechanisms. The aim of our study was to elucidate the pathogenesisofCharsyndromeatthemolecularlevel. Methodology/Principal Findings: GeneexpressionofTfap2bduring mousedevelopmentwasstudied, andnewborns of Tfap2b-deficient mice were examined to identify phenotypes. Gel shift assays had been carried out to search for Tfap2 downstream genes. Promoters of candidategenes werecloned into areporter construct andused todemonstrate their regulation by Tfap2b in cell transfection. In situ hybridizations showed that the murine transcription factor Tfap2b was expressedduringtheentiredevelopmentofmouseductusarteriosus.Histologicalexaminationofductusarteriosusfrom Tfap2bknockoutmice6hoursafterbirthrevealedthattheywerenotclosed.Consequently,thelungsofTfap2b2/2 mice demonstratedprogressivecongestionofthepulmonarycapillaries,whichwaspostulatedtoresultsecondarilyfromPDA.In addition,Tfap2bwasexpressedinthelimbbuds,particularlyintheposteriorlimbfieldduringdevelopment.LackofTfap2b resulted in bilateral postaxial accessory digits. Further study indicated that expressions of bone morphogenetic protein (Bmp)genes,whicharereportedtobeinvolvedinthelimbpatterningandductaldevelopment,werealteredinlimbbuds ofTfap2b-deficientembryos,duetod