biostudies-literature00510Pollen AASimons FoundationNICHD NIH HHSHoward Hughes Medical InstituteNIMH NIH HHSNINDS NIH HHSNIHBowes FoundationNIGMS NIH HHSDamon Runyon FoundationCIRMNIH HHS743-756.e17https://www.ebi.ac.uk/biostudies/studies/S-EPMC6544371biostudies-literatureUnknown176(4)Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Despite metabolic differences, organoid models preserve gene regulatory networks related to primary cell types and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoids and macaque cortex, enriched for recent gene duplications, and including multiple regulators of PI3K-AKT-mTOR signaling. We observed increased activation of this pathway in human radial glia, dependent on two receptors upregulated specifically in human: INSR and ITGB8. Our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.CellEstablishing Cerebral Organoids as Models of Human-Specific Brain Evolution.PMC6544371DRG-2166-13GC1R-06673-CR35 NS097305U01 MH105989P51 OD011132ORIP/OD P51OD011132T32 GM007266SFARI 491371T32 HD007470F32 NS103266F32 NS103266-02Mostajo-Radji MABhaduri ANowakowski TJMeyerson OSKronenberg ZNBershteyn MDougherty MLAlvarado BWest JAPollen AAHaussler DDi Lullo EAndrews MGBedolli MLowe CBFiddes ITLeyrat AAKriegstein AREichler EEShuga JPavlovic BJSalama SR51falseEstablishing Cerebral Organoids as Models of Human-Specific Brain Evolution.Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Despite metabolic differences, organoid models preserve gene regulatory networks related to primary cell types and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoids and macaque cortex, enriched for recent gene duplications, and including multiple regulators of PI3K-AKT-mTOR signaling. We observed increased activation of this pathway in human radial glia, dependent on two receptors upregulated specifically in human: INSR and ITGB8. Our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.2019-01-01T00:00:00Z2019 Feb2024-11-13T16:34:11.069Z2020-10-30T08:42:05ZS-EPMC65443713073563310.1016/j.cell.2019.01.017