Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution

Summary Direct comparisons of human and non-human primate brains can reveal molecular pathwaysunderlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain sizefirst appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoidsfrom chimpanzee. Despite metabolic differences, organoidmodels preserve gene regulatory networksrelated to primary celltypes and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoidsand 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 braindevelopment and evolution.