Conditional deletion of Hand2 reveals critical functions in neurogenesis and cell type-specific gene expression for development of neural crest-derived noradrenergic sympathetic ganglion neurons

摘要

Neuralcrest-derivedstructuresthatdependcriticallyuponexpressionofthebasichelixndash;loopndash;helixDNAbindingproteinemHand2/emfornormaldevelopmentincludecraniofacialcartilageandbone,theoutflowtractoftheheart,cardiaccushion,andnoradrenergicsympatheticganglionneurons.LossofemHand2/emisembryoniclethalbyE9.5,obviatingageneticanalysisofitsin-vivofunction.WehaveovercomethisdifficultybyspecificdeletionofemHand2/eminneuralcrest-derivedcellsbycrossingourlineoffloxedemHand2/emmicewithWnt1-Cretransgenicmice.OuranalysisofemHand2/emknock-outinneuralcrest-derivedcellsrevealseffectsondevelopmentinallneuralcrest-derivedstructureswhereemHand2/emisexpressed.Intheautonomicnervoussystem,conditionaldisruptionofemHand2/emresultsinasignificantandprogressivelossofneuronsaswellasasignificantlossofTHexpression.emHand2/emaffectsgenerationoftheneuralprecursorpoolofcellsbyaffectingboththeproliferativecapacityoftheprogenitorsaswellasaffectingexpressionofemPhox2a/emandemGata3/em,DNAbindingproteinsimportantforthecellautonomousdevelopmentofnoradrenergicneurons.OurdatasuggestthatemHand2/emisamultifunctionalDNAbindingproteinaffectingdifferentiationandcelltype-specificgeneexpressioninneuralcrest-derivednoradrenergicsympatheticganglionneurons.emHand2/emhasapivotalfunctioninanon-linearcross-regulatorynetworkofDNAbindingproteinsthataffectcellautonomouscontrolofdifferentiationandcelltype-specificgeneexpression./p/div