Induction of Expansion and Folding in Human Cerebral Organoids
Open accessAbstract
An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids. This genetic modification allows sustained cell cycle re-entry, expansion of the progenitor population, and delayed neuronal differentiation, all key features of the developing human cortex. In contrast, Pten deletion in mouse organoids does not lead to folding. Finally, we utilized the expanded cerebral organoids to show that infection with Zika virus impairs cortical growth and folding. Our study provides new insights into the mechanisms regulating the structure and organization of the human cortex.
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PTEN deletion and enhancement of PI3K-AKT growth signalling caused expansion and surface folding of cerebral organoids.
“A recent report described expansion and surface folding of cerebral organoids following phosphatase and tensin homologue (PTEN) deletion and enhancement of the phosphoinositide 3-kinase (PI3K)–AKT growth signalling pathway51, suggesting that increased neural progenitor proliferation may be a major contributing factor to expansion and gyrification of the human brain.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [51]
These genome-editing manipulations are easily applied to organoid systems.
“These manipulations are easily applied to organoid systems51,66, fuelling a burgeoning interest in the application of this technology to understand the pathophysiology of a wide range of adult and developmental human brain diseases.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [51]
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- Authors
- Li, Y., Muffat, J., Omer, A., Bosch, I., Lancaster, M. A., Sur, M., Gehrke, L., Knoblich, J. A., & Jaenisch, R.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Institute of Technology (US)
- Institute of Molecular Biotechnology (AT)
- Harvard University (US)
- Corresponding author
- Jaenisch, Rudolf
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 20
- Issue
- 3
- Pages
- 385-396.e3
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6461394
- OpenAlex
- W2565974502
- Cited by
- 436
- References
- 49
- Citations by year
- 2026: 20 · 2025: 30 · 2024: 55 · 2023: 43 · 2022: 58 · 2021: 57 · 2020: 66 · 2019: 46 · 2018: 36 · 2017: 25
- FWCI
- 18.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Simons Foundation (SFARI 204106, SFLIFE 286977)
- International Rett Syndrome Foundation
- Brain and Behavior Research Foundation
- European Leukodystrophy Association
- Jerome and Florence Brill
- NIH (HD 045022, R01-MH104610, R01-NS088538, AI100190)
- ELA Foundation
- Emerald Foundation
- Biogen
- Simons Center for the Social Brain
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- brain organoids, cortical folding, neocortex expansion, neural progenitor proliferation, PTEN deletion, cell cycle re-entry, Zika virus infection
- MeSH terms
- Zika Virus Infection, Zika Virus, Animals, Cell Differentiation, Cells, Cultured, Enzyme Activation, Humans, Neurons, Organoids, Gene Deletion, Intercellular Signaling Peptides and Proteins, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Cerebrum, Neural Stem Cells
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