Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution
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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.
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NPAS3 is differentially expressed in various cell types such as inhibitory neurons and astrocytes during development (human vs macaque) and also in adults (human vs chimpanzee/macaque).
“Comparative analysis of available transcriptomic data of human and non-human primates (chimpanzee and macaque [Sousa et al. 2017; Pollen et al. 2019; Khrameeva et al. 2020; Jorstad et al. 2023]) indicates that NPAS3 is differentially expressed in various cell types such as inhibitory neurons and astrocytes during development (human vs macaque) and also in adults (human vs. chimpanzee/macaque).”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Pollen et al. 2019
The Results section ('Human-specific gene expression changes'; page unavailable) reports differential expression between developing human and macaque cortex and between human and chimpanzee organoids. A search for NPAS3 found no passage establishing its differential expression in inhibitory neurons or astrocytes, and the cited comparisons do not address adult brains. The broader findings therefore cannot verify the NPAS3-specific claim. (LLM, conf=0.72)
Experimental — accuracy not yet measuredNPAS3 is not differentially expressed among two-month brain organoids from humans and chimpanzees.
“We found in this dataset that NPAS3 is not differentially expressed among two months-brain organoids from humans and chimpanzees”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Pollen et al. 2019
The Results section (“Human-specific gene expression changes”; page unavailable) reports a human–chimpanzee organoid differential-expression comparison, but does not state whether NPAS3 was differentially expressed. Searches for NPAS3, its full name, and two-month organoids found no passage establishing the claimed NPAS3 result. (LLM, conf=0.74)
Experimental — accuracy not yet measuredNPAS3 is differentially expressed in inhibitory neurons in macaque compared to human cortices.
“Among them, we found that NPAS3 is differentially expressed in inhibitory neurons in macaque compared to human cortices (supplementary fig. S14, Supplementary Material online; Pollen et al. 2019).”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Pollen et al. 2019
The Results section, “Human-specific gene expression changes” (page unavailable), reports differential expression between human and macaque cortical cells but does not identify NPAS3. A search for NPAS3 and inhibitory-neuron terms found discussion of inhibitory-neuron gene networks, not a human–macaque NPAS3 difference in those neurons. (LLM, conf=0.72)
Experimental — accuracy not yet measuredDirect comparisons between organoids and primary counterparts in mouse and human have quantified a notable similarity between neural progenitor and neuronal transcriptome profiles.
“Direct comparisons between organoids and primary counterparts in mouse and human have quantified a notable similarity between the neural progenitor and neuronal transcriptome profiles7–9.”
From Inferring and perturbing cell fate regulomes in human brain organoids (2023) · cites this paper as [9]
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Notaras, M., Lodhi, A., Dündar, F., Collier, P., Sayles, N. M., Tilgner, H., Greening, D., & Colak, D. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01316-6 · Cited by 150 · see citing works
Resolving organoid brain region identities by mapping single-cell genomic data to reference atlases
Fleck, J. S., Sanchís-Calleja, F., He, Z., Santel, M., Boyle, M. J., Camp, J. G., & Treutlein, B. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.02.015 · Cited by 118 · see citing works
Three-dimensional genome rewiring in loci with human accelerated regions
Keough, K. C., Whalen, S., Inoue, F., Przytycki, P. F., Fair, T., Deng, C., Steyert, M., Ryu, H., Lindblad-Toh, K., Karlsson, E., et al. (2023) · Science · doi:10.1126/science.abm1696 · Cited by 113 · see citing works
Self-citationA catalog of single nucleotide changes distinguishing modern humans from archaic hominins
Kuhlwilm, M., & Boeckx, C. (2019) · Scientific Reports · doi:10.1038/s41598-019-44877-x · Cited by 108 · see citing works
Human neuronal maturation comes of age: cellular mechanisms and species differences
Wallace, J. L., & Pollen, A. A. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00760-3 · Cited by 82 · see citing works
Self-citationCellular and Molecular Mechanisms Linking Human Cortical Development and Evolution
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Single cell epigenomic atlas of the developing human brain and organoids
Ziffra, R. S., Kim, C. N., Wilfert, A., Turner, T. N., Haeussler, M., Casella, A. M., Przytycki, P. F., Kreimer, A., Pollard, K. S., Ament, S. A., et al. (2019) · doi:10.1101/2019.12.30.891549 · Cited by 33 · see citing works
Self-citationMetabolic mechanisms of species-specific developmental tempo
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The sociability spectrum: evidence from reciprocal genetic copy number variations
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Human-specific genetic hallmarks in neocortical development: focus on neural progenitors
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- Authors
- Pollen, A. A., Bhaduri, A., Andrews, M. G., Nowakowski, T. J., Meyerson, O. S., Mostajo-Radji, M. A., Di Lullo, E., Alvarado, B., Bedolli, M., Dougherty, M. L., Fiddes, I. T., Kronenberg, Z. N., Shuga, J., Leyrat, A. A., West, J. A., Bershteyn, M., Lowe, C. B., Pavlovic, B. J., Salama, S. R., Haussler, D., Eichler, E. E., & Kriegstein, A. R.
- Affiliations
- University of California, San Francisco (US)
- University of Washington (US)
- University of California, Santa Cruz (US)
- Standard BioTools (United States) (US)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pollen, Alex A.
- Kriegstein, Arnold R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 176
- Issue
- 4
- Pages
- 743-756.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6544371
- OpenAlex
- W2905157186
- Cited by
- 600
- References
- 67
- Citations by year
- 2026: 55 · 2025: 76 · 2024: 80 · 2023: 84 · 2022: 86 · 2021: 95 · 2020: 86 · 2019: 37
- FWCI
- 28.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- CIRM (GC1R-06673-C)
- Damon Runyon Foundation (DRG-2166-13)
- NIH (U01 MH105989, F32 NS103266-02)
- Simons Foundation (SFARI 491371)
- Bowes Foundation (ORIP/OD P51OD011132)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- brain organoids, human brain evolution, chimpanzees, macaque, neocortical neurogenesis, pluripotent stem cells, gene regulatory networks, gene duplication, PI3K/AKT/mTOR pathway, radial glia, insulin receptor
- MeSH terms
- Animals, Brain, Cell Differentiation, Cerebral Cortex, Pan troglodytes, Biological Evolution, Humans, Macaca, Organoids, Species Specificity, Cell Culture Techniques, Pluripotent Stem Cells, Gene Regulatory Networks, Neurogenesis, Induced Pluripotent Stem Cells, Single-Cell Analysis, Transcriptome
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