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Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing
Open accessPublished version of a preprint
Abstract
Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.
Overview
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Written from the paper’s full text.
TL;DR
Deep single-cell RNA sequencing of 1,816 mouse brain myeloid cells across embryonic, early postnatal, and adult stages shows that adult homeostatic microglia are transcriptionally similar across brain regions, whereas early postnatal microglia are more heterogeneous. The authors identify proliferative region-associated microglia (PAM), a transient white-matter subset that shares a gene signature with degenerative disease-associated microglia, is TREM2/APOE-independent, and phagocytoses newly formed oligodendrocytes.
Key findings
- Adult homeostatic microglia show limited regional transcriptomic heterogeneity: fewer than 20 genes were differentially expressed in cluster 0 adult microglia between regions (FDR < 0.05), and bulk RNA-seq of TMEM119+ microglia from cortex, cerebellum, hippocampus, and striatum was highly correlated (R > 0.99) with no differentially expressed genes between regions (FDR < 0.05).
- Early postnatal microglia are more heterogeneous; after cell cycle regression, P7 microglia resolved into three clusters, including P7-C1/PAM, which expressed DAM-associated genes such as Spp1, Gpnmb, Clec7a, Lpl, Cd9, Cd63, Lgals3, Fabp5, Itgax, Apoe, and Tyrobp.
- PAM appeared mainly in developing corpus callosum and cerebellar white matter, peaked around P7, were amoeboid, and phagocytosed newly formed oligodendrocytes; PAM were still present in P7 Trem2−/− or Apoe−/− white matter, unlike DAM.
- Cell cycle pseudotime identified 315 periodically expressed genes for P7-C0 and 347 for P7-C1, with 183 overlapping genes; many newly identified genes were not previously described as periodically expressed.
Methods
- Smart-seq2 scRNA-seq was performed on index-sorted innate immune cells from mouse brain at E14.5, P7, and P60; P7 and P60 cells were isolated from cortex, cerebellum, hippocampus, striatum, olfactory bulb, and choroid plexus. In total, 1,922 cells were sequenced to at least 1 million raw reads per cell, and 1,816 cells (94.5%) passed QC: 142 E14.5, 978 P7, and 696 P60 cells.
- Unsupervised Seurat clustering yielded 15 clusters, including 7 microglia clusters; analyses included differential expression, cell cycle regression, pseudotime reconstruction, gene network construction, and bulk RNA-seq of TMEM119+ adult microglia.
- Validation used RNAscope, immunohistochemistry, FACS, a pH-sensitive bead phagocytosis assay on acute brain slices, and Trem2−/− and Apoe−/− mice.
Limitations
- The paper states that additional brain regions beyond the 4 major regions tested may uncover transcriptomic differences, and that microglial heterogeneity may also be represented by electrophysiological, epigenetic, or functional measurements; future work is needed to distinguish whether PAM are transcriptionally pre-disposed to phagocytosis or represent a transient phenotypic conversion.
- Evident from the text: all experiments used male mice; the IEG+ microglia cluster is likely an experimental artifact from cell extraction/sorting, since Fos/Egr1 were not detected in adult microglia on tissue sections.
- Evident from the text: PAM phagocytosis evidence is largely histological and correlative, although the slice phagocytosis assay supports preferential phagocytic capacity in corpus callosum and cerebellar white matter.
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In the paper
“early postnatal microglia, which were distributed among clusters 0–5”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phase-specific gene expression of dividing microglia along cell cycle pseudotime
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In the paper
“In total, we identified 315 periodically expressed genes for P7-C0 cells, and 347 genes for P7-C1 cells”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phase-specific gene expression of dividing microglia along cell cycle pseudotime
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In the paper
“CP MΦ were separated into two distinct clusters (cluster 7 and cluster 9) largely confined to their developmental stages”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Postnatal transcriptional alteration of choroid plexus macrophages
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In the paper
“P7-C2 was a small cluster that mainly included cells clustered together with embryonic E14.5 microglia (cluster 5) in the initial analysis”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Heterogeneity of early postnatal microglia revealed by scRNA-seq
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In the paper
“By contrast, early postnatal microglia are more heterogeneous.”
- Also stated in: § Introduction · plain
“we observed much higher heterogeneity in early postnatal microglia.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Abstract
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In the paper
“are metabolically active”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Abstract
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In the paper
“the majority of newly identified genes appeared in at least one of the four datasets”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phase-specific gene expression of dividing microglia along cell cycle pseudotime
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In the paper
“PAM also displayed distinct cytokine/chemokine secretion profiles, including Ccl3 and Ccl4”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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In the paper
“we found that certain genes previously attributed to microglial regional heterogeneity were largely expressed by different populations of non-microglial cells from our scRNA-seq data”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Limited transcriptomic heterogeneity of adult homeostatic microglia
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In the paper
“adult microglia were almost exclusively present in cluster 0 and cluster 6”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Limited transcriptomic heterogeneity of adult homeostatic microglia
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- It may state two separate claims as one. 47
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In the paper
“We found that three interconnected gene modules explained P7 microglia identities and, more importantly, many DAM signature genes occupied the “hub” positions in the network.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Heterogeneity of early postnatal microglia revealed by scRNA-seq
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In the paper
“we identified many genes that have yet to be described as periodically expressed in dividing cells (“Novel”), although more than half of these new genes have possible links to cell proliferation based on gene function annotations”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phase-specific gene expression of dividing microglia along cell cycle pseudotime
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In the paper
“scRNA-seq data suggested that this P7-C1 population also had higher levels of Igf1 and Itgax expression. Indeed, we detected co-expression of both transcripts in Gpnmb-positive cells”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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In the paper
“We identified H2-Eb1 and Lilra5 as molecular markers for adult CP MΦ and Clec4n for their postnatal counterparts, and validated this selective gene expression by RNA in situ and immunohistochemistry”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Postnatal transcriptional alteration of choroid plexus macrophages
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In the paper
“scRNA-seq of microglia freshly isolated based on GPNMB and CLEC7A co-expression validated the original gene expression pattern observed with the initial P7 clustering results; the clustering algorithm also reported another GPNMB+CLEC7A+ concentrated cluster which overlapped with a portion of P7-C1 cells”
- Also stated in: § Validation of early postnatal proliferative region-associated microglia · plain
“This new double positive cluster expressed all the markers identified in P7-C1, just at higher levels on average”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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- Also stated in: § Validation of early postnatal proliferative region-associated microglia · plain
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In the paper
“We discovered a proliferative region-associated microglia (PAM) subset, mainly found in developing white matter, that share a characteristic gene signature with degenerative disease-associated microglia (DAM).”
- Also stated in: § Heterogeneity of early postnatal microglia revealed by scRNA-seq · plain
“P7-C1 microglia exhibited characteristic expression of many genes that have recently been shown to be up-regulated in degenerative disease-associated microglia (DAM) (Keren-Shaul et al., 2017; Krasemann et al., 2017).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Abstract
What the sources say
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- Also stated in: § Heterogeneity of early postnatal microglia revealed by scRNA-seq · plain
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In the paper
“Spp1 was detected in close to 100% of the double positive cells by scRNA-seq, and SPP1 only labeled a portion of CLEC7A+ cells on tissue sections”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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In the paper
“samples from cortex, cerebellum, hippocampus and striatum were highly correlated (R>0.99), and individual samples did not cluster according to tissue origins”
- Also stated in: § Limited transcriptomic heterogeneity of adult homeostatic microglia · hedged
“we could not detect any differentially expressed genes (FDR < 0.05) between regions from the bulk samples”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Limited transcriptomic heterogeneity of adult homeostatic microglia
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- Also stated in: § Limited transcriptomic heterogeneity of adult homeostatic microglia · hedged
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In the paper
“early postnatal PAM and periventricular myeloid cells specifically expressed CLEC7A protein”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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In the paper
“Compared with cluster 0, only 27 total genes (including P2ry12) were differentially expressed in cluster 6, out of which half were immediate early genes (IEG)”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Limited transcriptomic heterogeneity of adult homeostatic microglia
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In the paper
“This included 7 microglia clusters, 2 choroid plexus macrophage clusters, 3 monocyte clusters and 3 other immune or epithelial cell clusters”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Clustering of brain myeloid cells across developmental stages by deep scRNA-seq
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In the paper
“these three clusters largely corresponded to the three dominant cell cycle-independent clusters (cluster 1, 2 and 5) found in the original analysis, and the two original cycling clusters (cluster 3 and 4) were simply redistributed among P7-C0, P7-C1 and P7-C2 following cell cycle regression”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phase-specific gene expression of dividing microglia along cell cycle pseudotime
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In the paper
“P7-C1 microglia exhibited characteristic expression of many genes that have recently been shown to be up-regulated in degenerative disease-associated microglia (DAM)”
- Also stated in: § Heterogeneity of early postnatal microglia revealed by scRNA-seq · plain
“up-regulation of the disease genes was accompanied by down-regulation of the homeostatic gene cassette”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Heterogeneity of early postnatal microglia revealed by scRNA-seq
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- Also stated in: § Heterogeneity of early postnatal microglia revealed by scRNA-seq · plain
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In the paper
“RNA in situ labeling demonstrated that expression of these two genes overlapped almost exclusively in the corpus callosum and cerebellar white matter (marked by Mbp+ oligodendrocytes), and that Spp1+Gpnmb+ cells were positive for the microglia marker Cx3cr1”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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In the paper
“Cells belonging to P7-C2 expressed microglial signature genes at lower levels (e.g. Tmem119, Selplg, P2ry12, Tgfbr1), and displayed up-regulation of genes in metal homeostasis (Fth1, Ftl1, Mt1), actin cytoskeleton dynamics (Tmsb4x, Pfn1, Cfl1), and ribosomal components (e.g. Rps14, Rps18, Rpl35, Rps29)”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Heterogeneity of early postnatal microglia revealed by scRNA-seq
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In the paper
“Only in the adult CP MΦ cluster (cluster 7) did we detect high levels of MHC-II gene expression”
- Also stated in: § Postnatal transcriptional alteration of choroid plexus macrophages · plain
“By contrast, postnatal CP MΦ (cluster 9) expressed many genes that function in endocytosis and intracellular trafficking”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Postnatal transcriptional alteration of choroid plexus macrophages
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- Also stated in: § Postnatal transcriptional alteration of choroid plexus macrophages · plain
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In the paper
“Starting at P4, CLEC7A+ microglia populated the corpus callosum and cerebellar white matter (Figure 7A), and they continued to expand and peaked around P7 (Figures 6E and 7B). By P14, these white matter PAM were barely detectable”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Transient appearance of PAM in developing white matter, independent of TREM2 or APOE
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In the paper
“we discovered that CLEC7A+ microglia were associated transiently with the developing white matter, and found in regions of neurogenesis”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Transient appearance of PAM in developing white matter, independent of TREM2 or APOE
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In the paper
“We found that only microglia in the corpus callosum and cerebellum white matter (mostly CLEC7A+) preferentially phagocytosed beads (Figures 8C, 8D, S7A, and S7B), and this phenomenon was independent of opsonizing factors or other components in serum (Figure 8D).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
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In the paper
“From the scRNA-seq data, Mbp and Gfap transcripts were detected in certain percentages of P7-C1 (32/323=9.9% for Mbp; 5/323=1.5% for Gfap) and P7-GPNMB+CLEC7A+ microglia (26/192=13.5% for Mbp; 17/192=8.9% for Gfap), while Pdgfra counts were zero in all P7 microglia (Figure 8I).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
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In the paper
“We discovered that one trajectory pointed towards the development of early postnatal PAM, while the other pointed towards homeostatic, mature cells”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
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In the paper
“We showed here that early postnatal PAM are not a general intermediate step for microglia development, but mainly transiently appear in the developing white matter.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
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In the paper
“We showed that early postnatal PAM display unique cytokine/chemokine profiles and express many trophic factors including Igf1, Spp1, Lgals1, and Lgals3 (Figure S5D).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
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In the paper
“During the late embryonic (E17.5) stage, CLEC7A+ microglia appeared almost exclusively in the neurogenic niches near the lateral ventricles (Figure 7A), while CLEC7A−IBA1+ cells were present throughout the brain parenchyma.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Transient appearance of PAM in developing white matter, independent of TREM2 or APOE
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In the paper
“The timing of their appearance coincides with the onset of myelination, during which large numbers of newly formed oligodendrocytes die (Barres et al., 1992; Trapp et al., 1997).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
What the sources say
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In the paper
“CLEC7A+ microglia in the P7 white matter were amoeboid in shape and had thicker primary branches with larger cell bodies (Figures 7E–7G). By contrast, CLEC7A−microglia in the cortex were much more ramified.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Transient appearance of PAM in developing white matter, independent of TREM2 or APOE
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In the paper
“we followed up on our histological observation that CLEC7A+ microglia in the developing white matter had amoeboid shapes and frequently contained pyknotic nuclei (Figures 8A and 8B; Movie S1).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
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In the paper
“More importantly, we observed early postnatal PAM containing cleaved Caspase-3 (cCASP3)-positive inclusions, which were MBP positive and possessed pyknotic nuclei (Figures 8E, 8F, and S7E; Movie S2).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
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In the paper
“In addition, we could not find cCASP3+ Aldh1l1-GFP labeled astrocytes, although substantial interactions between astrocytes and early postnatal PAM existed (Figures 8H, S7D, and S7F).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because the detection rates for P7-C0 microglia (8/274=2.9% for Mbp; 2/274=0.7% for Gfap) were more than 2 folds lower for both genes (P<0.001 for either gene, Chi-squared test), these differences were unlikely due to mRNA contamination during cell isolation.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
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In the paper
“Similar results were observed with higher percentages.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
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In the paper
“Indeed, adult microglia stained negative for Fos/Egr1 transcripts or proteins, whereas their expression was readily detected in the surrounding non-microglial cells”
- Also stated in: § Limited transcriptomic heterogeneity of adult homeostatic microglia · hedged
“if we consider the contribution of IEGs to the clustering result as an experimental artifact”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Limited transcriptomic heterogeneity of adult homeostatic microglia
What the sources say
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- Also stated in: § Limited transcriptomic heterogeneity of adult homeostatic microglia · hedged
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting a developmental phenotypic switch for these particular brain resident macrophages.”
- Also stated in: § Postnatal transcriptional alteration of choroid plexus macrophages · boosted
“CP MΦ are a second example of brain resident macrophages that undergo a postnatal transcriptional alteration.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Postnatal transcriptional alteration of choroid plexus macrophages · boosted
In the paper
“We compared these machine-reported gene lists with four published datasets for experimentally characterized cell cycle genes (including the HeLa data we used as seeds) (Grant et al., 2013)”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phase-specific gene expression of dividing microglia along cell cycle pseudotime
What the sources say
- Not checked yetcites Grant et al., 2013 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“we performed region-specific bulk RNA-seq of highly purified homeostatic microglia sorted with TMEM119 antibodies, which label over 90% of microglia in the adult brain (Bennett et al., 2016).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Limited transcriptomic heterogeneity of adult homeostatic microglia
What the sources say
- Not checked yetcites Bennett et al., 2016 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Amoeboid morphology has indeed been associated with a phagocytic state in microglia or macrophages (Bohlen et al., 2017; Ling and Wong, 1993).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
What the sources say
- Not checked yetcites Bohlen et al., 2017 source
- Not checked yetcites Ling and Wong, 1993
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“All animal studies were performed with approval from the Stanford Administrative panel on Laboratory Animal Care in accordance with institutional and national regulations.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Alternatively, these phagocytes may promote cell death to sculpt tissue structures and create functional circuits (Fuchs and Steller, 2011).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
What the sources say
- Not checked yetcites Fuchs and Steller, 2011 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“we analyzed the sequencing results for External RNA Controls Consortium (ERCC) Spike-In RNA, and found that our Smart-seq2 platform had nearly single molecule detection limit and high precision (R=0.98)”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Clustering of brain myeloid cells across developmental stages by deep scRNA-seq
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Alternatively, the act of phagocytosis may drive or reinforce the expression of genes associated with lipid metabolism, lysosomal functions and phagocytosis.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We used a recently developed protocol for cell extraction to minimize microglial activation (Bennett et al., 2016).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Clustering of brain myeloid cells across developmental stages by deep scRNA-seq
What the sources say
- Not checked yetcites Bennett et al., 2016 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This indicates high levels of energy turnover, particularly lipid metabolism, in PAM that may be required for phagocytosis of lipid-rich oligodendrocytes.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that postnatal immature microglia can either turn on genes specific for classical microglia found in the adult brain (P60-homeostatic) or assume the PAM phenotype (P7-C1 and P7-GPNMB+CLEC7A+) similar to DAM in aging and neurodegeneration”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Validation of early postnatal proliferative region-associated microglia
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is thus possible that efficient engulfment of newly formed oligodendrocytes by PAM in the developing white matter is necessary to generate evenly spaced oligodendrocyte tiling and to make room for myelination.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, microglia in the midbrain have been shown to possess distinct gene expression profiles compared with cortical microglia (De Biase et al., 2017).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
What the sources say
- Not checked yetcites De Biase et al., 2017 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Male mice were used in all experiments.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, while early postnatal PAM engulf newly formed oligodendrocytes and possibly newborn astrocytes during development, DAM are also phagocytic and involved in phagocytosis of Aβ plaques in AD models (Keren-Shaul et al., 2017; Krasemann et al., 2017).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“our study detected about 3 times as many genes per cell, and produced higher detection rates for over 80% of genes”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Clustering of brain myeloid cells across developmental stages by deep scRNA-seq
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been shown that transcriptional changes in degenerative disease-associated microglia depend on the TREM2-APOE pathway, and the DAM signature genes such as Spp1, Gpnmb and Clec7a are suppressed in disease models that also lack Trem2 or Apoe (Keren-Shaul et al., 2017; Krasemann et al., 2017).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Transient appearance of PAM in developing white matter, independent of TREM2 or APOE
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that this phagocytic activity mainly targets newly formed oligodendrocytes but not their precursors.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Microglial heterogeneity can also be represented by measurements other than gene transcription, such as electrophysiological properties, epigenetic features or functional readouts (Ayata et al., 2018; De Biase et al., 2017).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, additional brain regions may uncover transcriptomic differences not present in the 4 major regions tested here.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Discussion
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data suggest that early postnatal PAM phagocytose newly formed oligodendrocytes and perhaps to a lesser extent, astrocytes.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > Results > Phagocytosis of newly formed oligodendrocytes by early postnatal PAM
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Processing of RNA-seq data and clustering analysis were performed blinded, and cell identities were unblinded when combining the meta data into the analysis pipeline. Genotype information was blinded when analyzing PAM presence in the wild type, Trem2−/− or Apoe−/− mutant mouse brains.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“We used a previously published algorithm to estimate sensitivity and accuracy of scRNA-seq data based on ERCC spike-ins with known concentrations (Svensson et al., 2017).”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
What the sources say
- Not checked yetcites Svensson et al., 2017 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“For the bulk RNA-seq data, we included 3 biological replicates for each brain region in our analysis. All of the histology experiments (RNA in situ or immunohistochemistry) were performed on at least 3 individual animals, and repeated at least twice.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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 scRNA-seq data analysis, we applied 3 statistical criteria in the quality control workflow to exclude cells that had low sequencing reads (poor RNA recovery), low numbers of detected genes (low complexity of libraries), or low ERCC correlation coefficients (insufficient accuracy) using the methods described below.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“To ensure the phase label for each remaining gene is applicable to microglia, correlations between its expression and the average expression of each gene set were calculated, and the gene was assigned to the gene set that had the maximal correlation with it. The correlation examination and re-assignment were run iteratively until no more genes were re-assigned.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“Permutation was repeated for 1.0e+05 times to generate a distribution of permutation differences, with which the observed difference was compared to calculate a p-value.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“For bulk RNA-seq, all 3 replicates for each region were prepared identically and included in the analysis. They generated sequencing results with similar read counts and numbers of detected genes.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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 sequencing or histology experiments, randomly chosen wild type or mutant mice that were housed under the same condition were used.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“For the scRNA-seq data, we pooled samples from multiple mice to generate the gene expression atlas followed by histology validation.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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
“After filtering, 1816 cells, out of 1922, were retained.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The number of cells for scRNA-seq and the number of replicates for bulk RNA-seq were empirically determined based on previous studies (Darmanis et al., 2015; Tabula Muris et al., 2018; Zhang et al., 2014). The used sample-size in scRNA-seq allowed us to robustly identify cell populations as small as 20 cells.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“During the iteration, the initial gene seeds were always kept in the updated list for the next round to avoid random drifting by noise.”
§ Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing > STAR Methods > METHOD DETAILS
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Little is known about the molecular heterogeneity of microglia under physiological conditions, especially during development.
“Despite the importance of these multitasking cells, little is known about their molecular heterogeneity under physiological conditions and especially during development when they perform many critical non-immune functions.”
The paper relies on this without support.
It is unclear whether there are molecularly defined subtypes of microglia in the adult brain and how they are distributed across brain regions.
“it remains unclear whether there are molecularly defined subtypes of microglia in the adult brain and, if so, how they are distributed across brain regions.”
The paper relies on this without support.
How extensive microglial heterogeneity is, and what it does in the developing and mature healthy brain, is still unclear.
“The extent of microglial heterogeneity and its functional significance in the developing and mature homeostatic brain, however, remains elusive.”
The paper relies on this without support.
Professional phagocytes must remove dying or dead cells to keep tissue homeostasis.
“Dying or dead cells need to be cleared away by professional phagocytes in order to maintain tissue homeostasis.”
The paper relies on this without support.
During development of multicellular organisms, excess cells are commonly produced and then removed by controlled apoptosis.
“Overproduction of cells, balanced by controlled apoptosis, is a common theme during development of multicellular organisms, although the biological significance behind this is often unknown.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recently, it has been shown that several subsets of microglia with unique molecular and functional phenotypes exist in the healthy, aged, and degenerating brain3–5.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations.”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [108]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent experiments using deep sequencing revealed differences not only depending on the brain region, but also on age, gender, and pathology [28,39,99,102,108,109].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [108]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These clusters were identified based on the expression of known cell type–specific markers: microglia (clusters 0 to 6 and 10), T cells (cluster 7), macrophages (clusters 8 and 9), neutrophils (cluster 12), and B cells (cluster 14) (Fig. 8A and table S5) (40, 41).”
From Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Indeed, the microglia population is highly heterogeneous, comprised of cells in discrete transcriptional dynamic “substates” that appear in defined contexts and brain regions [333,334,335,336].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [336]
Experimental — accuracy not yet measured
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In the citing paper
“many of which were well documented61–66.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [61]
Experimental — accuracy not yet measuredIn the citing paper
“AP1B1 is part of the clathrin-associated adaptor protein complex AP-1 and is involved in endocytosis and intracellular trafficking (81).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [81]
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Metadata
- Authors
- Li, Q., Cheng, Z., Zhou, L., Darmanis, S., Neff, N. F., Okamoto, J., Gulati, G., Bennett, M. L., Sun, L. O., Clarke, L. E., Marschallinger, J., Yu, G., Quake, S. R., Wyss-Coray, T., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Virginia Tech (US)
- Stanford University (US)
- Corresponding author
- Li, Qingyun
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 101
- Issue
- 2
- Pages
- 207-223.e10
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6336504
- OpenAlex
- W2949996247
- Cited by
- 1,129
- References
- 54
- Citations by year
- 2026: 102 · 2025: 158 · 2024: 163 · 2023: 174 · 2022: 153 · 2021: 185 · 2020: 122 · 2019: 67
- FWCI
- 42.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- JPB Foundation
- Adelson Medical Research Foundation
- Vincent J. Coates Foundation
- NIH (R01 DA015043, R01 MH110504)
- Veterans Administration
- NOMIS Foundation
- Helen Hay Whitney Foundation
- National Multiple Sclerosis Society
- Life Science Research Foundation
- Stanford Medicine Dean’s Fellowship
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, microglial heterogeneity, brain development, white matter development, amoeboid microglia, microglial transcriptome, mouse brain, innate immunity
- MeSH terms
- Algorithms, Animals, Animals, Newborn, Brain, Choroid Plexus, Computer Simulation, Embryo, Mammalian, Mice, Inbred C57BL, Mice, Transgenic, Oligodendroglia, Phagocytosis, Antigens, CD, Cluster Analysis, Sequence Analysis, RNA, Microglia, Gene Expression Regulation, Developmental, Myeloid Cells, Cell Proliferation, Mice, Gene Regulatory Networks, High-Throughput Nucleotide Sequencing, Transcriptome
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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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