Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans 英文参考文献.docVIP

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Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans 英文参考文献.doc

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Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans 英文参考文献

PathologicandPhenotypicAlterationsinaMouse ExpressingaConnexin47MissenseMutationThatCauses Pelizaeus-Merzbacher–LikeDiseaseinHumans OliverTress1,MartaMaglione2,ArminZlomuzica3,DennisMay1,NikolaiDicke1,JoachimDegen1 ,Ekrem Dere4,HelmutKettenmann2,DieterHartmann5,KlausWillecke1* 1InstituteofGenetics,DivisionofMolecularGenetics,UniversityofBonn,Bonn,Germany,2CellularNeurosciences,Max-Delbru¨ckCenterforMolecularMedicine,Berlin, Germany,3CenterfortheStudyandTreatmentofMentalHealth,Ruhr-Universita¨t Bochum,Bochum,Germany,4Universite′ PierreetMarieCurie(ParisVI),UMR7102, NeurobiologiedesProcessusAdaptatifs,Paris,France,5DepartmentofAnatomy,DivisionofNeuroanatomy,UniversityofBonn,Bonn,Germany Abstract Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites.Humanoligodendrocytesexpressthegapjunctionproteinconnexin47(Cx47),whichisencodedbytheGJC2 gene.TheautosomalrecessivemutationhCx47M283TcausesPelizaeus-Merzbacher–likedisease1(PMLD1),aprogressive leukodystrophycharacterizedbyhypomyelination,retardedmotordevelopment,nystagmus,andspasticity.Weintroduced thehumanmissensemutationintotheorthologouspositionofthemouseGjc2geneandinsertedthemCx47M282Tcoding sequenceintothemousegenomeviahomologousrecombinationinembryonicstemcells.Three-week-oldhomozygous Cx47M282Tmicedisplayedimpairedrotarodperformancebutunchangedopen-fieldbehavior.10-15-day-oldhomozygous Cx47M282TandCx47nullmicerevealedamorethan80%reductioninthenumberofcellsparticipatinginglialnetworks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resultedinreducedMBPexpressionandastrogliosisinthecerebellumoften-day-oldmicewhichcouldalsobedetectedin Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behaviornorimpairedrotarodperformanceanymore.AdultmCx47M282Texpressingmicedidnotshowsubstantialmyelin alterations, but homozygous