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1、ARTICLEdoi:10.1038/nature12517Cerebralorganoidsmodelhumanbraindevelopmentandmicrocephaly112123MadelineA.Lancaster,MagdalenaRenner,Carol-AnneMartin,DanielWenzel,LouiseS.Bicknell,MatthewE.Hurles,4121TessaHomfray,JosefM.Penninger,AndrewP.Jackson&JuergenA.KnoblichThecomplexityof
2、thehumanbrainhasmadeitdifficulttostudymanybraindisordersinmodelorganisms,highlightingtheneedforaninvitromodelofhumanbraindevelopment.Herewehavedevelopedahumanpluripotentstemcell-derivedthree-dimensionalorganoidculturesystem,termedcerebralorganoids,thatdevelopvariousdiscrete,
3、althoughinterdependent,brainregions.Theseincludeacerebralcortexcontainingprogenitorpopulationsthatorganizeandproducematurecorticalneuronsubtypes.Furthermore,cerebralorganoidsareshowntorecapitulatefeaturesofhumancorticaldevelopment,namelycharacteristicprogenitorzoneorganizati
4、onwithabundantouterradialglialstemcells.Finally,weuseRNAinterferenceandpatient-specificinducedpluripotentstemcellstomodelmicrocephaly,adisorderthathasbeendifficulttorecapitulateinmice.Wedemonstrateprematureneuronaldifferentiationinpatientorganoids,adefectthatcouldhelptoexpla
5、inthediseasephenotype.Together,thesedatashowthatthree-dimensionalorganoidscanrecapitulatedevelopmentanddiseaseeveninthismostcomplexhumantissue.Mammalianbraindevelopmentbeginswiththeexpansionoftheneuro-ofregionalidentitiesorganizedasdiscretedomainscapableofinfluen-1epithelium
6、togenerateradialglialstemcells(RGs).TheseRGsdivideatcingoneanother.Furthermore,cerebralcorticalregionsdisplayanorgani-theapicalsurfacewithintheventricularzone(VZ)togenerateneuronszationsimilartothedevelopinghumanbrainatearlystages,aswellasandintermediateprogenitors.Intermedi
7、ateprogenitorspopulatethethepresenceofaconsiderableoRGpopulation.Moreover,cerebraladjacentsubventricularzone(SVZ),whereasneuronsmigratethroughcorticalneuronsmaturetoformvariouspyramidalidentitieswiththeintermediatezonetopopulatespecificlayerswithinthecorticalplate.modestspat
8、ialseparation.Finally,weusepatient-derivedinducedInhumans,theorganizationof
