The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
Assembly of functionally integrated human forebrain spheroids
Open accessAbstract
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca V 1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
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In the citing paper
“With their 3D structures and cell components resembling the human brain, these organoids can replicate the complex brain microenvironment better than 2D in vitro models (15–17, 19)”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredIn the citing paper
“The ‘extrinsic’ organoid model whereby patterning is influenced by externally added molecules rather than relying on intrinsic self-organization shows promise with regard to better reproducibility5,6,25.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“These findings were further supported by another report documenting interneuron migration following fusion of dorsal and ventral brain organoids26, and both studies demonstrated disruption of migration by antagonism of C-X-C chemokine receptor type 4 (CXCR4), which has an important role in interneuron migration6,26.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“In the dorsal-ventral fused model mentioned earlier6, cells that migrated from the subpallial spheroid to the cortical spheroid expressed cortical interneuron markers, and whole-cell voltage-clamp recordings demonstrated that these interneuron-like cells can receive excitatory inputs from cells in the dorsal cortical organoids; conversely, the cells in the dorsal cortical organoids can receive”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“The organoid-derived interneurons migrated in a manner similar to that of their in vivo counterparts.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“The cells that had migrated into the cortical spheroids also fired action potentials at twice the rate of cells in unfused subpallial spheres or non-migrated cells in the fused organoid, suggesting maturation of membrane properties.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“For example, the fusion of human cortical spheroids and human subpallial spheroids was used to model the migration of interneurons from the subpallium to the cortex6.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“This revealed a cell-autonomous migration defect in Timothy syndrome-derived interneurons.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [6]
In the citing paper
“Brain organoid models have been shown to recapitulate cell proliferation effects in microcephaly (Thomas et al., 2017) and have been used to study neural migration defects in Timothy syndrome, a rare ASD form caused by mutations in the Cav1.2 calcium channel gene (Birey et al., 2017).”
From Getting to the cores of autism (2019) · cites this paper as Birey et al., 2017
In the citing paper
“We have previously developed an approach to model complex cellular interactions during human brain development by specifying region-specific spheroids or organoids and then fusing them in vitro to generate three-dimensional (3D) assembloids”
From Generation of Functional Human 3D Cortico-Motor Assembloids (2020) · cites this paper as Birey et al., 2017
In the citing paper
“We previously described the generation of 3D spheroids resembling the cerebral cortex (human cortical spheroids [hCS]) (Birey et al., 2017; Paşca et al., 2015; Sloan et al., 2017, 2018), which contain deep and superficial glutamatergic neurons.”
From Generation of Functional Human 3D Cortico-Motor Assembloids (2020) · cites this paper as Birey et al., 2017
In the citing paper
“We verified expression of cortico-spinal-associated markers in hCS, including FEZF2, BCL11B (CTIP2), and SOX5, using single-cell profiling of hCS (Birey et al., 2017) and found a population of cells co-expressing these genes in the glutamatergic neuron cluster but not in a subpallial-derived GABAergic cluster”
From Generation of Functional Human 3D Cortico-Motor Assembloids (2020) · cites this paper as Birey et al., 2017
In the citing paper
“We previously showed the potential of using region-specific spheroids as a modular approach to study human interneuron migration and identify disease phenotypes (Birey et al., 2017).”
From Generation of Functional Human 3D Cortico-Motor Assembloids (2020) · cites this paper as Birey et al., 2017
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Citations
Cites
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Spatial reconstruction of single-cell gene expression data
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F., & Regev, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3192 · Cited by 7,055
Cerebral organoids model human brain development and microcephaly
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., & Knoblich, J. A. (2013) · Nature · doi:10.1038/nature12517 · Cited by 5,372
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Model of autism: increased ratio of excitation/inhibition in key neural systems
Rubenstein, J. L. R., & Merzenich, M. M. (2003) · Genes, Brain and Behavior · doi:10.1034/j.1601-183x.2003.00037.x · Cited by 2,768
Cited by
Sorted by citations
Human organoids: model systems for human biology and medicine
Kim, J., Koo, B.-K., & Knoblich, J. A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0259-3 · Cited by 2,187
Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity
Welch, J. D., Kozareva, V., Ferreira, A., Vanderburg, C., Martin, C., & Macosko, E. Z. (2019) · Cell · doi:10.1016/j.cell.2019.05.006 · Cited by 1,193
Hofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184
Individual brain organoids reproducibly form cell diversity of the human cerebral cortex
Velasco, S., Kedaigle, A. J., Simmons, S. K., Nash, A., Rocha, M., Quadrato, G., Paulsen, B., Nguyen, L., Adiconis, X., Regev, A., et al. (2019) · Nature · doi:10.1038/s41586-019-1289-x · Cited by 1,094
Trujillo, C. A., Gao, R., Negraes, P. D., Gu, J., Buchanan, J., Preissl, S., Wang, A., Wu, W., Haddad, G. G., Chaim, I. A., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.08.002 · Cited by 974
Metadata
- Authors
- Birey, F., Andersen, J., Makinson, C. D., Islam, S., Wei, W., Huber, N., Fan, H. C., Metzler, K. R. C., Panagiotakos, G., Thom, N., O’Rourke, N. A., Steinmetz, L. M., Bernstein, J. A., Hallmayer, J., Huguenard, J. R., & Paşca, S. P.
- Affiliations
- Stanford Medicine (US)
- University of California, San Francisco (US)
- ORCID
- Venue
- Nature
- Published
- 2017-04-26
- Volume
- 545
- Issue
- 7652
- Pages
- 54-59
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5805137
- OpenAlex
- W2609473806
- Cited by
- 1,365
- References
- 58
- Citations by year
- 2026: 148 · 2025: 169 · 2024: 164 · 2023: 135 · 2022: 161 · 2021: 165 · 2020: 168 · 2019: 135 · 2018: 84 · 2017: 34
- FWCI
- 48.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R33MH100717, R01MH107800, R01MH100900)
- National Human Genome Research Institute (P01HG000205)
- National Institute of Neurological Disorders and Stroke (R01NS090911, R01NS034774)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- human pluripotent stem cells, GABAergic interneurons, interneuron migration, Timothy syndrome, Cav1.2 calcium channel, glutamatergic neurons, brain organoids, neural development
- MeSH terms
- Autistic Disorder, Cell Line, Cell Movement, Cells, Cultured, Female, Humans, Interneurons, Long QT Syndrome, Male, Models, Biological, Neurons, Synapses, Syndactyly, Prosencephalon, Glutamic Acid, Spheroids, Cellular, Pluripotent Stem Cells, Neurogenesis, GABAergic Neurons
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