The DOI matches its Crossref record; 67 of the 68 references it cites were found in a registry or an index; none of the 20 sources its claims cite is checked for support yet.
CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons
Open accessPublished version of a preprint
Abstract
CRISPR/Cas9-based functional genomics have transformed our ability to elucidate mammalian cell biology. However, most previous CRISPR-based screens were conducted in cancer cell lines rather than healthy, differentiated cells. Here, we describe a CRISPR interference (CRISPRi)-based platform for genetic screens in human neurons derived from induced pluripotent stem cells (iPSCs). We demonstrate robust and durable knockdown of endogenous genes in such neurons and present results from three complementary genetic screens. First, a survival-based screen revealed neuron-specific essential genes and genes that improved neuronal survival upon knockdown. Second, a screen with a single-cell transcriptomic readout uncovered several examples of genes whose knockdown had strikingly cell-type-specific consequences. Third, a longitudinal imaging screen detected distinct consequences of gene knockdown on neuronal morphology. Our results highlight the power of unbiased genetic screens in iPSC-derived differentiated cell types and provide a platform for systematic interrogation of normal and disease states of neurons. VIDEO ABSTRACT.
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57 Own result · 24 Own method · 9 Own interpretation · 8 Not checked yet
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“We demonstrate robust and durable knockdown of endogenous genes in such neurons”
- Also stated in: § Robust CRISPR interference in human iPSC-derived neurons · boosted
“Our platform thus enables potent CRISPRi knockdown of endogenous genes in iPSC-derived neurons.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > Abstract
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- Also stated in: § Robust CRISPR interference in human iPSC-derived neurons · boosted
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In the paper
“or activity as evaluated by calcium imaging (Fig. S1F and Movies S1, S2).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Robust CRISPR interference in human iPSC-derived neurons
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“We found that expression of CRISPRi machinery and/or sgRNAs did not cause detectable DNA damage (Fig. S1C,D)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Robust CRISPR interference in human iPSC-derived neurons
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In the paper
“the vast majority of sgRNAs that altered survival in pooled screens also altered survival in our arrayed longitudinal survival analysis (Fig. 7D).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > An arrayed CRISPRi platform for rich phenotyping by longitudinal imaging
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“The vast majority of neuron-essential genes were detectable at the transcript level, further supporting the specificity of our screen results.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > A pooled CRISPRi screen reveals neuron-essential genes
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“we observed that two independent sgRNAs targeting PPP1R12C each caused continued proliferation instead of neuronal differentiation in a subset of iPSCs (Fig. S4F,G)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Inducible CRISPRi distinguishes neuronal differentiation and survival phenotypes
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“By clustering gene knockdown groups based on the signature of differential gene expression, we found transcriptomic signatures associated with knockdown of functionally related genes (Fig. 4C).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > CROP-Seq generates mechanistic hypotheses for genes controlling neuronal survival
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“hierarchical clustering of individual sgRNAs based on these features led to coclustering of the two sgRNAs targeting a given gene for the majority of genes (Fig. 7E).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > An arrayed CRISPRi platform for rich phenotyping by longitudinal imaging
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“we identified a small number of genes, including PPCDC, UROD and MAT2A, for which knockdown was less toxic in the presence of astrocytes (Fig. 3F).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Pooled validation of hit genes
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In the paper
“We validated the strong neuronal dependence on the cholesterol biogenesis pathway pharmacologically using the HMG-CoA reductase inhibitor mevastatin (Fig. 2E)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > A pooled CRISPRi screen reveals neuron-essential genes
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In the paper
“and did not affect neuronal differentiation (Fig. S1E)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Robust CRISPR interference in human iPSC-derived neurons
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In the paper
“This analysis revealed a shared core set of essential genes, as expected, and additional iPSC-specific and neuron-specific essential genes (Fig. 2D).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > A pooled CRISPRi screen reveals neuron-essential genes
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“only a few genes, including SQLE, MMAB, MVK, UQCRQ, and ATP5B, showed high similarity (similarity score > 0.15) in the transcriptomic changes they induced in iPSCs versus neurons. Knockdown of most genes induced distinct transcriptomic responses in the two cell types.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > CROP-Seq reveals neuron-specific transcriptomic consequences of gene knockdown
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In the paper
“MAT2A is essential in neurons, but not iPSCs (Fig. 6B).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > CROP-Seq reveals neuron-specific transcriptomic consequences of gene knockdown
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In the paper
“sgRNAs targeting PPP1R12C were strongly enriched when TMP was added at the iPSC stage, but this phenotype was substantially weaker when TMP was added at the neuron stage.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Inducible CRISPRi distinguishes neuronal differentiation and survival phenotypes
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In the paper
“MAP3K12 knockdown caused downregulation of a vast array of proteins involved in cytoskeletal organization, and upregulation of specific synaptotagmins”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > CROP-Seq generates mechanistic hypotheses for genes controlling neuronal survival
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Ribosomal genes and the anti-apoptotic transcription factor Brn3a (encoded by POU4F1) were upregulated.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > CROP-Seq generates mechanistic hypotheses for genes controlling neuronal survival
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Knockdown phenotypes of hit genes were strongly correlated between neurons at different time points, but distinctly less correlated between neurons and iPSCs (Fig. 2C).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > A pooled CRISPRi screen reveals neuron-essential genes
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In the paper
“In both iPSCs and neurons, all positive hits and most of the negative hits from the primary screen were confirmed in the validation screen (Fig. 3C).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > Pooled validation of hit genes
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In the paper
“or neurite growth (Fig. S6C).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > An arrayed CRISPRi platform for rich phenotyping by longitudinal imaging
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In the paper
“We found that neither CRISPRi machinery nor non-targeting sgRNAs affected neuronal survival (Fig. S6B)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > An arrayed CRISPRi platform for rich phenotyping by longitudinal imaging
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In the paper
“knockdown of the essential E1 ubiquitin activating enzyme, UBA1 (Fig. 5B)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > CROP-Seq reveals neuron-specific transcriptomic consequences of gene knockdown
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In the paper
“Median number of genes detected per cell was around 5,000 for iPSCs and 4,600 for neurons.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“The mean reads per cell was around 84,000 for iPSCs and 91,000 for neurons.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“which yields large quantities of highly homogeneous neurons, a prerequisite for robust population-based screens.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > INTRODUCTION
What the sources say
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In the paper
“induced expression of different transcription factors yield other types of neurons, such as motor neurons (Hester et al., 2011; Shi et al., 2018) and inhibitory neurons (Yang et al., 2017).”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > DISCUSSION
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In the paper
“Despite their usefulness, iPSC-derived neurons have limitations – in particular, they do not fully recapitulate all features of mature (or aging) neurons in the human brain.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > DISCUSSION
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In the paper
“Second, it is inducible and reversible (Gilbert et al., 2014)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > DISCUSSION
What the sources say
- Not checked yetcites Gilbert et al., 2014 source
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In the paper
“our large-scale CRISPRi screen in human iPSC-derived neurons uncovered genes that control the survival of neurons, but not cancer cells or iPSCs”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > RESULTS > A pooled CRISPRi screen reveals neuron-essential genes
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In the paper
“Neurons are a highly specialized and disease-relevant cell type, and thus it is crucial to study certain human gene functions in these cells.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > DISCUSSION
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In the paper
“In addition to the Ngn2-driven generation of glutamatergic neurons (Fernandopulle et al., 2018; Wang et al., 2017; Zhang et al., 2013) used here”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > DISCUSSION
What the sources say
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In the paper
“CRISPRi-i3N iPSCs were transduced with the pool at 70% MOI (quantified as fraction of BFP-positive cells by flow cytometry) and were transduced cells selected by 1 ug/ml of puromycin to obtain a population of cells that was ~85% BFP-positive.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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In the paper
“the library representation was ~35,000 cells / library element on Day 14 and ~28,000 cells / library element on Day 28.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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In the paper
“For a given cell, sgRNA(s) whose UMI counts were greater than 4 standard deviations of the mean UMI counts of all sgRNAs were assigned to that cell as its identity.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“approximately 2 million of these cells were harvested as Day 0 sample (corresponding to a library representation of ~9,000 cells/library element)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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In the paper
“Cells with only one assigned sgRNA were retained for further analysis.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“a gene was discarded if it was targeted by two sgRNAs and the correlation of the two sgRNAs was less than 0.8.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“The initial MOI, quantified as the fraction of BFP-positive cells by flow cytometry, was ~15%, corresponding to a library representation of ~450 cells per library element.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Day 14 neurons from each replicate of co-culture experiment were harvested, the library representation was ~50,000 neurons/library element.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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In the paper
“Approximately 2 million of Day 10 iPSCs from each replicate were harvested, corresponding to a library representation of ~9,000 cells/library element.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CRISPRi-i3 N iPSCs were infected with a pool of selected sgRNAs in the CROP-Seq vector pMK1334 at a low multiplicity of infection to minimize double infection.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“192 sgRNAs, including 184 sgRNAs targeting 92 selected hit genes from the primary screen (two sgRNAs per gene) and 8 non-targeting control sgRNAs, were individually cloned into the secondary screening vector pMK1334 and verified by Sanger sequencing.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“the estimated library representation for these time points was ~410 cells/library element on Day 14, ~380 cells/library element on Day 21, and ~330 cells/library element on Day 28.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For each target gene, the top 50% cells with best on-target knockdown were retained.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Subsequently, knockdown phenotype scores for each sgRNA were calculated as LFCs of sgRNA counts between two samples and were normalized by subtracting the median of non-targeting control sgRNAs.”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At the end of treatment, cells were assessed by flow cytometry (83% expressed high levels of BFP)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The AAVS1 locus, where the inducible Ngn2 transgene was integrated, lies within the PPP1R12C gene.
“Interestingly, the AAVS1 locus, into which the inducible Ngn2 transgene was integrated, resides within the PPP1R12C gene.”
The paper relies on this without support.
Primary human neurons are difficult to obtain from human donors and cannot be expanded because they are post-mitotic.
“primary neurons are difficult to obtain from human donors, and non-expandable due to their post-mitotic nature.”
The paper relies on this without support.
Most previous CRISPR-based screens were conducted in cancer cell lines or stem cells rather than healthy differentiated human cells.
“Most previous CRISPR-based screens were implemented in cancer cell lines or stem cells rather than healthy differentiated human cells”
The paper relies on this without support.
CRISPRi reduces gene function by partial knockdown rather than complete knockout, allowing study of essential genes.
“Furthermore, CRISPRi perturbs gene function by partial knockdown, rather than knockout, thereby enabling the investigation of the biology of essential genes.”
The paper relies on this without support.
sgRNA abundance in pooled screens reflects cell survival or proliferation.
“Based on the depletion or enrichment of sgRNAs targeting specific genes at different time points compared to day 0, we identified hit genes for which knockdown was toxic or beneficial to either iPSCs or neurons at different time points (Fig. 2B, Fig. S2B).”
The paper relies on this without support.
iPSCs can be made from readily available cells, genetically engineered, expanded, and differentiated into various cell types.
“They can be made from readily available cells, such as skin fibroblasts or peripheral mononuclear blood cells; they can be genetically engineered and subsequently expanded to generate large numbers of isogenic cells; and they can then be differentiated into a variety of cell types”
The paper relies on this without support.
The presence of astrocytes in co-culture is representative of the brain environment.
“In the brain, many neuronal functions are supported by glial cells, particularly astrocytes.”
The paper relies on this without support.
CRISPR interference reduces gene expression partially rather than completely eliminating it.
“Third, it perturbs gene function via partial knockdown, as opposed to knockout”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“This approach was pioneered in mammalian cells using RNA interference80,81, but CRISPR-based platforms have enabled the generation of substantially larger genetic interaction maps82, including CRISPRa-based gain-of-function maps83 and maps that combine gain- and loss-of-function perturbations to map directional pathways84.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [82]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
“resuspended in Cortical Neuron Culture Medium with doxycycline (2 ug/uL)”
§ CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
“and optionally 2μg/mL doxycycline.”
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Self-citationAdditional file 4 of An integrated toolkit for human microglia functional genomics
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Additional file 8 of An integrated toolkit for human microglia functional genomics
Haq, I., Ngo, J. C., Roy, N., Pan, R., Nawsheen, N., Chiu, R., Zhang, Y., Fujita, M., Soni, R. K., Wu, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26704728
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Self-citation
Metadata
- Authors
- Tian, R., Gachechiladze, M. A., Ludwig, C. H., Laurie, M. T., Hong, J. Y., Nathaniel, D., Prabhu, A. V., Fernandopulle, M. S., Patel, R., Abshari, M., Ward, M. E., & Kampmann, M.
- Affiliations
- University of California, San Francisco (US)
- National Institutes of Health (US)
- Corresponding author
- Ward, Michael E.
- Kampmann, Martin
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 104
- Issue
- 2
- Pages
- 239-255.e12
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6813890
- OpenAlex
- W2967789674
- Cited by
- 543
- References
- 68
- Citations by year
- 2026: 85 · 2025: 116 · 2024: 103 · 2023: 60 · 2022: 66 · 2021: 62 · 2020: 45 · 2019: 6
- FWCI
- 15.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of General Medical Sciences
- Paul G. Allen Family Foundation
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- CRISPR interference, iPSC-derived neurons, functional genetic screens, gene knockdown, neuronal survival, essential genes, single-cell transcriptomics, neuronal morphology
- MeSH terms
- RNA-Seq, Cell Survival, Humans, Neurons, Microscopy, Confocal, Gene Knockdown Techniques, Induced Pluripotent Stem Cells, Single-Cell Analysis, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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