Gata3 Acts Downstream of β-Catenin Signaling to Prevent Ectopic Metanephric Kidney Induction 英文参考文献.docVIP

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Gata3 Acts Downstream of β-Catenin Signaling to Prevent Ectopic Metanephric Kidney Induction 英文参考文献.doc

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Gata3 Acts Downstream of β-Catenin Signaling to Prevent Ectopic Metanephric Kidney Induction 英文参考文献

Gata3ActsDownstreamofb-CateninSignalingto PreventEctopicMetanephricKidneyInduction DavidGrote1,2,SamiKamelBoualia1,2,AbdallahSouabni3,CalliMerkel4,5,XuanChi6,FrankCostantini6, ThomasCarroll4,5,MaximeBouchard1,2 * 1GoodmanCancerCentre,McGillUniversity,Montreal,Quebec,Canada,2DepartmentofBiochemistry,McGillUniversity,Montreal,Quebec,Canada,3ResearchInstitute ofMolecularPathology,ViennaBiocenter,Vienna,Austria,4DepartmentofInternalMedicine,UniversityofTexasSouthwesternMedicalCenteratDallas,Dallas,Texas, United States in America, 5Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States in America, 6DepartmentofGeneticsandDevelopment,ColumbiaUniversityMedicalCenter,NewYork,NewYork,UnitedStatesinAmerica Abstract Metanephrickidneyinductioncriticallydependsonmesenchymal–epithelialinteractionsinthecaudalregionofthenephric (orWolffian)duct.Centraltothisprocess,GDNFsecretedfromthemetanephricmesenchymeinducesureterbuddingby activatingtheRetreceptorexpressedinthenephricductepithelium.Afailuretoregulatethispathwayisbelievedtobe responsibleforalargeproportionofthedevelopmentalanomaliesaffectingtheurogenitalsystem.Here,weshowthatthe nephric duct-specific inactivation of the transcription factor gene Gata3 leads to massive ectopic ureter budding. This resultsinaspectrumofurogenitalmalformationsincludingkidneyadysplasia,duplexsystems,andhydroureter,aswellas vas deferens hyperplasia and uterine agenesis. The variability of developmental defects is reminiscent of the congenital anomaliesofthekidneyandurinarytract(CAKUT)observedinhuman.WeshowthatGata3inactivationcausespremature nephric duct cell differentiation and loss of Ret receptor gene expression. These changes ultimately affect nephric duct epitheliumhomeostasis,leadingtoectopicbuddingofinterspersedcellsstillexpressingtheRetreceptor.Importantly,the formationoftheseectopicbudsrequiresbothGDNF/RetandFgfsignalingactivities.WefurtheridentifyGata3asacentral mediatorofb-