A human tissue screen identifies a regulator of ER secretion as a brain-size determinant
Abstract
Functional screen for microcephaly genes: Genetic screens are widely used to identify regulators in biological processes. Human screens are currently limited to two-dimensional cell cultures, which lack the ability to score tissue-dependent gene function. Esk et al. combined CRISPR-Cas9 screening with barcoded cellular lineage tracing to enable loss-of-function screening in three-dimensional human cerebral organoid tissue. By testing microcephaly candidate genes, the endoplasmic reticulum was found to control extracellular matrix protein secretion regulating tissue integrity and brain size. This genetic screen in human brain tissue implicates multiple pathways in microcephaly and provides a tool for systematic testing of genes in organoids. Science , this issue p. 935
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Enhanced specificity SpCas9 (eCas9) has substantially reduced off-target effects.
“we used a human embryonic stem cell (hES cell) line expressing an enhanced specificity SpCas9 (eCas9), which has substantially reduced off-target effects and is controlled by an upstream loxp stop element12”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [12]
Human brain tissues exhibit generation of clones with highly variable sizes both in vivo and in vitro.
“It is important to note that the development of human brain tissues exhibits the generation of clones with highly variable sizes both in vivo and in vitro12,19.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [12]
CRISPR screening combined with organoids has revealed power for discovering new gene functions.
“Recent studies combining CRISPR screening technology with organoids have revealed the power of such strategies for discovering new gene functions12,13.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [12]
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Single-cell brain organoid screening identifies developmental defects in autism
Li, C., Fleck, J. S., Martins-Costa, C., Burkard, T. R., Themann, J., Stuempflen, M., Peer, A. M., Vertesy, Á., Littleboy, J. B., Esk, C., et al. (2023) · Nature · doi:10.1038/s41586-023-06473-y · Cited by 283 · see citing works
“Generation of barcoded CHOOSE lentiviral pool, hESCs infection and EB generation The CHOOSE lentiviral vector was constructed based on a previously published lentiviral vector which carries a CAG driving ERT2-Cre-ERT2-P2A-EGFP-P2Apuro cassette (13).”
BackgroundMethodInfluentialSelf-citationCellular and Molecular Mechanisms Linking Human Cortical Development and Evolution
Libé-Philippot, B., & Vanderhaeghen, P. (2021) · Annual Review of Genetics · doi:10.1146/annurev-genet-071719-020705 · Cited by 78 · see citing works
- Authors
- Esk, C., Lindenhofer, D., Haendeler, S., Wester, R. A., Pflug, F., Schroeder, B., Bagley, J. A., Elling, U., Zuber, J., von Haeseler, A., & Knoblich, J. A.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- University of Vienna (AT)
- Research Institute of Molecular Pathology (AT)
- Center for Integrative Bioinformatics Vienna (CIBIV), Max F. Perutz Laboratories, University of Vienna and Medical University of Vienna, VBC, Vienna, Austria.
- Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
- Corresponding author
- Esk, Christopher
- Lindenhofer, Dominik
- ORCID
- Venue
- Science
- Published
- 2020-11-20
- Volume
- 370
- Issue
- 6519
- Pages
- 935-941
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3094954466
- Cited by
- 170
- References
- 5
- Citations by year
- 2026: 14 · 2025: 33 · 2024: 32 · 2023: 32 · 2022: 30 · 2021: 27 · 2020: 2
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Molecular Biology Organization (ALTF (966-2010))
- H2020 European Research Council (695642)
- Austrian Academy of Sciences
- Austrian Science Fund (F 7803-B, SFB-F78 P04)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- microcephaly, brain size, endoplasmic reticulum, brain organoids, CRISPR-Cas9 screen, loss-of-function screening, tissue integrity, human brain tissue
- MeSH terms
- Brain, Carrier Proteins, Cell Line, Endoplasmic Reticulum, Genetic Testing, Humans, Membrane Proteins, Microcephaly, Organ Size, Organoids, Extracellular Matrix Proteins, Cell Lineage, Gene Knockout Techniques, CRISPR-Cas Systems
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