Spatial Analysis of Expression Patterns Predicts Genetic Interactions at the Mid-Hindbrain Boundary 英文参考文献.docVIP

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Spatial Analysis of Expression Patterns Predicts Genetic Interactions at the Mid-Hindbrain Boundary 英文参考文献.doc

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Spatial Analysis of Expression Patterns Predicts Genetic Interactions at the Mid-Hindbrain Boundary 英文参考文献

SpatialAnalysisofExpressionPatternsPredictsGenetic InteractionsattheMid-HindbrainBoundary DominikM.Wittmann1,2,FlorianBlo¨chl1,DietrichTru¨mbach3,4,WolfgangWurst3,4,NilimaPrakash3, FabianJ.Theis1,2,5 * 1ComputationalModelinginBiology,InstituteforBioinformaticsandSystemsBiology,HelmholtzZentrumMu¨nchen,GermanResearchCentreforEnvironmentalHealth, Munich-Neuherberg, Germany, 2Zentrum Mathematik, Technische Universita¨t Mu¨nchen, Garching, Germany, 3Molecular Neurogenetics, Institute of Developmental Genetics,HelmholtzZentrumMu¨nchen,GermanResearchCentreforEnvironmentalHealth,TechnischeUniversita¨tMu¨nchen,DeutschesZentrumfu¨rNeurodegenerative Erkrankungen(DZNE),Munich-Neuherberg,Germany,4MaxPlanckInstituteofPsychiatry,Munich,Germany,5Max-Planck-InstituteforDynamicsandSelf-Organization, Go¨ttingen,Germany Abstract Theisthmicorganizermediatingdifferentiationofmid-andhindbrainduringvertebratedevelopmentischaracterizedbya well-definedpatternoflocallyrestrictedgeneexpressiondomainsaroundthemid-hindbrainboundary(MHB).Thispatternis established and maintained by a regulatory network between several transcription and secreted factors that is not yet understoodinfulldetail.InthiscontributionweshowthataBooleananalysisofthecharacteristicspatialgeneexpression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computationallogicfortheminimizationofBooleanfunctions.Thisapproachallowsustopredictalsotheinterplayofthe various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression,anissuethatremainedunclearfrompublisheddata.Usingmouseanteriorneuralplate/tubeexplantcultures, weprovideexperimentalevidencethatFgf8infactonlymaintainsbutdoesnotinduceectopicWnt1expressioninthese explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory networkbetweenkeytranscriptionandsecretedfactorsattheMHB.Analy