Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution.

Publication Year: 
Alex A Pollen
Aparna Bhaduri
Madeline G Andrews
Tomasz J Nowakowski
Olivia S Meyerson
Mohammed A Mostajo-Radji
Elizabeth Di Lullo
Beatriz Alvarado
Melanie Bedolli
Max L Dougherty
Ian T Fiddes
Zev N Kronenberg
Joe Shuga
Anne A Leyrat
Jay A West
Marina Bershteyn
Craig B Lowe
Bryan J Pavlovic
Sofie R Salama
David Haussler
Evan E Eichler
Arnold R Kriegstein
PubMed link: 
Public Summary: 
Scientific Abstract: 
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.