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Amplification of human interneuron progenitors promotes brain tumors and neurological defects
Open accessPublished version of a preprint
Abstract
Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.
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“We used previously established protocols that reproducibly generate human telencephalon organoids23,24 (Extended Data Fig. 5a–c).”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [24]
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Metadata
- Authors
- Eichmüller, O. L., Corsini, N. S., Vértesy, Á., Morassut, I., Scholl, T., Gruber, V.-E., Peer, A. M., Chu, J., Novatchkova, M., Hainfellner, J. A., Paredes, M. F., Feucht, M., & Knoblich, J. A.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- Medical University of Vienna (AT)
- University of California, San Francisco (US)
- Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences, Vienna Biocenter (VBC), Vienna, Austria.
- Corresponding author
- Corsini, Nina S.
- ORCID
- Venue
- Science
- Published
- 2022-01-28
- Volume
- 375
- Issue
- 6579
- Pages
- eabf5546-eabf5546
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7613689
- OpenAlex
- W4210452888
- Cited by
- 163
- References
- 79
- Citations by year
- 2026: 19 · 2025: 38 · 2024: 35 · 2023: 38 · 2022: 25
- FWCI
- 12.57
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- European Commission (695642)
- Österreichischen Akademie der Wissenschaften (SFB F78)
- Bundesministerium für Bildung, Wissenschaft und Forschung
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute (P50CA097257)
- National Institute of Neurological Disorders and Stroke (P01NS083513, DP2NS122550)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- tuberous sclerosis complex, malformations of cortical development, brain organoids, neural stem cells, brain tumors, epilepsy, developmental delay, epidermal growth factor receptor inhibition, human brain evolution
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, RNA-Seq, Brain, Brain Neoplasms, Humans, Interneurons, Organoids, Tuberous Sclerosis, Disease Progression, Cell Lineage, Loss of Heterozygosity, Gene Expression Profiling, Cell Proliferation, Induced Pluripotent Stem Cells, TOR Serine-Threonine Kinases, Neural Stem Cells, Carcinogenesis, ErbB Receptors
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