Antagonistic Interplay between Necdin and Bmi1 Controls Proliferation of Neural Precursor Cells in the Embryonic Mouse Neocortex.docVIP

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Antagonistic Interplay between Necdin and Bmi1 Controls Proliferation of Neural Precursor Cells in the Embryonic Mouse Neocortex.doc

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Antagonistic Interplay between Necdin and Bmi1 Controls Proliferation of Neural Precursor Cells in the Embryonic Mouse Neocortex

AntagonisticInterplaybetweenNecdinandBmi1 ControlsProliferationofNeuralPrecursorCellsinthe EmbryonicMouseNeocortex RyoheiMinamide,KazushiroFujiwara,KoichiHasegawa,KazuakiYoshikawa* LaboratoryofRegulationofNeuronalDevelopment,InstituteforProteinResearch,OsakaUniversity,Suita,Osaka,Japan Abstract Neuralprecursorcells(NPCs)intheneocortexexhibitahighproliferationcapacityduringearlyembryonicdevelopmentand give rise to cortical projection neurons after maturation. Necdin, a mammal-specific MAGE (melanoma antigen) family protein that possesses anti-mitotic and pro-survival activities, is expressed abundantly in postmitotic neurons and moderatelyintissue-specificstemcellsorprogenitors.NecdininteractswithE2FtranscriptionfactorsandsuppressesE2F1- dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex. Necdin is moderately expressed in the ventricular zone of mouseembryonicneocortex,inwhichproliferativecellpopulationsaresignificantlyincreasedinnecdin-nullmice.Inthe neocortex of necdin-null embryos, expression of Cdk1 and Sox2, a stem cell marker, is significantly increased, whereas expression of p16, a cyclin-dependent kinase inhibitor, is markedly diminished. Cdk1 and p16 expression levels are also significantlyincreasedanddecreased,respectively,inprimaryNPCspreparedfromnecdin-nullembryos.Intriguingly,necdin interactsdirectlywithBmi1,aPolycombgroupproteinthatsuppressesp16expressionandpromotesNPCproliferation.In HEK293Acellstransfectedwithluciferasereporterconstructs,necdinrelievesBmi1-dependentrepressionofp16promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity. In lentivirus- infected primary NPCs, necdin overexpression increases p16 expression, suppresses Cdk1 expression, and inhibits NPC proliferation, whereas Bmi1 overexpression suppresses p16 expression, increases Cdk1 expression, and promotes