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Cell. 2019 Feb 7;176(4):743-756.e17. doi: 10.1016/j.cell.2019.01.017.

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

Author information

1
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.
2
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.
3
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Anatomy, UCSF, San Francisco, CA, USA.
4
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
5
Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
6
New Technologies, Fluidigm, South San Francisco, CA, USA.
7
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA, USA.
8
Department of Developmental Biology, Stanford University, Stanford, CA, USA.
9
Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA; Howard Hughes Medical Institute, UC Santa Cruz, Santa Cruz, CA, USA.
10
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
11
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: arnold.kriegstein@ucsf.edu.

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.

KEYWORDS:

cerebral organoids; chimpanzee; cortical development; human-specific evolution; mTOR; macaque; neural progenitor cells; radial glia; single-cell RNA sequencing

PMID:
30735633
DOI:
10.1016/j.cell.2019.01.017

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