Distinct Roles of Hand2 in Initiating Polarity and Posterior Shh Expression during the Onset of Mouse Limb Bud Development 英文参考文献.docVIP

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Distinct Roles of Hand2 in Initiating Polarity and Posterior Shh Expression during the Onset of Mouse Limb Bud Development 英文参考文献.doc

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Distinct Roles of Hand2 in Initiating Polarity and Posterior Shh Expression during the Onset of Mouse Limb Bud Development 英文参考文献

DistinctRolesofHand2inInitiatingPolarityand PosteriorShhExpressionduringtheOnsetofMouse LimbBudDevelopment AntonellaGalli1¤a*,DimitriRobay1,MarcoOsterwalder1,XiaozhongBao2,Jean-DenisBe′nazet1, MuhammadTariq3¤b,RenatoParo3,4,SusanMackem2,RolfZeller1* 1DevelopmentalGenetics,DepartmentofBiomedicine,UniversityofBasel,Basel,Switzerland,2CancerandDevelopmentalBiologyLaboratory,NationalCancerInstitute, Bethesda,Maryland,UnitedStatesofAmerica,3DepartmentofBiosystemsScienceandEngineering,ETHZurich,Basel,Switzerland,4FacultyofSciences,Universityof Basel,Basel,Switzerland Abstract Thepolarizationofnascentembryonicfieldsandtheendowmentofcellswithorganizerpropertiesarekeytoinitiationof vertebrate organogenesis. One such event is antero-posterior (AP) polarization of early limb buds and activation of morphogenetic Sonic Hedgehog (SHH) signaling in the posterior mesenchyme, which in turn promotes outgrowth and specifiesthepentadactylousautopod.InactivationoftheHand2transcriptionalregulatorfromtheonsetofmouseforelimb buddevelopment disruptsestablishment ofposterioridentityand Shhexpression, whichresultsinaskeletalphenotype identicaltoShhdeficientlimbbuds.Inwild-typelimbbuds,Hand2ispartoftheproteincomplexescontainingHoxd13, anotheressentialregulatorofShhactivationinlimbbuds.ChromatinimmunoprecipitationshowsthatHand2-containing chromatin complexes are bound to the far upstream cis-regulatory region (ZRS), which is specifically required for Shh expression in the limb bud. Cell-biochemical studies indicate that Hand2 and Hoxd13 can efficiently transactivate gene expression via the ZRS, while the Gli3 repressor isoform interferes with this positive transcriptional regulation. Indeed, analysisofmouseforelimbbudslackingbothHand2andGli3revealsthecompleteabsenceofantero-posterior(AP)polarity along the entire proximo-distal axis and extreme digit polydactyly without AP identities. Our study uncovers essential componentsofthetranscriptionalmachineryandkeyinteractionsthatset-uplimbbudasym