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Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution. 2019
Alex A Pollen, and
Aparna Bhaduri, and
Madeline G Andrews, and
Tomasz J Nowakowski, and
Olivia S Meyerson, and
Mohammed A Mostajo-Radji, and
Elizabeth Di Lullo, and
Beatriz Alvarado, and
Melanie Bedolli, and
Max L Dougherty, and
Ian T Fiddes, and
Zev N Kronenberg, and
Joe Shuga, and
Anne A Leyrat, and
Jay A West, and
Marina Bershteyn, and
Craig B Lowe, and
Bryan J Pavlovic, and
Sofie R Salama, and
David Haussler, and
Evan E Eichler, and
Arnold R Kriegstein
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA, USA. Electronic address: alex.pollen@ucsf.edu.
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.
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