ApoER2 and VLDLr Are Required for Mediating Reelin Signalling Pathway for Normal Migration and Positioning of Mesencephalic Dopaminergic Neurons.docVIP

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ApoER2 and VLDLr Are Required for Mediating Reelin Signalling Pathway for Normal Migration and Positioning of Mesencephalic Dopaminergic Neurons.doc

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ApoER2 and VLDLr Are Required for Mediating Reelin Signalling Pathway for Normal Migration and Positioning of Mesencephalic Dopaminergic Neurons

ApoER2andVLDLrAreRequiredforMediatingReelin SignallingPathwayforNormalMigrationandPositioning ofMesencephalicDopaminergicNeurons AhmedSharaf1,HansH.Bock2,3,Bjo¨rnSpittau1,ElisabethBouche′2,KerstinKrieglstein1* 1Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Albert-Ludwigs-Universita¨t, Freiburg, Germany, 2Center for Neuroscience, Albert- Ludwigs-Universita¨t, Freiburg,Germany,3DepartmentofMedicineII,Albert-Ludwigs-Universita¨t, Freiburg,Germany Abstract Themigrationofmesencephalicdopaminergic(mDA)neuronsfromthesubventricularzonetotheirfinalpositionsinthe substantianigracompacta(SNc),ventraltegmentalarea(VTA),andretrorubralfield(RRF)iscontrolledbysignallingfrom neurotrophicfactors,celladhesionmolecules(CAMs)andextracellularmatrixmolecules(ECM).Reelinandthecytoplasmic adaptor protein Disabled-1 (Dab1) have been shown to play important roles in the migration and positioning of mDA neurons. Mice lacking Reelin and Dab1 both display phenotypes characterised by the failure of nigral mDA neurons to migrate properly. ApoER2 and VLDLr are receptors for Reelin signalling and are therefore part of the same signal transductionpathwayasDab1.HerewedescribetherolesofApoER2andVLDLrinthepropermigrationandpositioningof mDA neurons in mice. Our results demonstrate that VLDLr- and ApoER2-mutant mice have both a reduction in and abnormalpositioningofmDAneurons.ThisphenotypewasmorepronouncedinVLDLr-mutantmice.Moreover,weprovide evidence that ApoER2/VLDLr double-knockout mice show a phenotype comparable with the phenotypes observed for Reelin-andDab1-mutantmice.Takentogether,ourresultsdemonstratethattheReelinreceptorsApoER2andVLDLrplay essentialrolesinReelin-mediatedmigrationandpositioningofmDAneurons. Citation: Sharaf A, Bock HH, Spittau B, Bouche′ E, Krieglstein K (2013) ApoER2 and VLDLr Are Required for Mediating Reelin Signalling Pathway for Normal MigrationandPositioningofMesencephalicDopaminergicNeurons.PLoSONE8(8):e71091.doi:10.1371/journal.pone.00