The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
New tools for studying microglia in the mouse and human CNS
Open accessAbstract
Significance: Microglia are the tissue resident macrophages of the brain and spinal cord, implicated in important developmental, homeostatic, and disease processes, although our understanding of their roles is complicated by an inability to distinguish microglia from related cell types. Although they share many features with other macrophages, microglia have distinct developmental origins and functions. Here we validate a stable and robustly expressed microglial marker for both mouse and human, transmembrane protein 119 (Tmem119). We use custom-made antibodies against Tmem119 to perform deep RNA sequencing of developing microglia, and demonstrate that microglia mature by the second postnatal week in mice. The antibodies, cell isolation methods, and RNAseq profiles presented here will greatly facilitate our understanding of microglial function in health and disease.
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“TMEM119 and P2RY12 are especially useful, since they have been shown to be expressed solely by microglial cells and not by infiltrating macrophages [41,42,43].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [41]
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
“The phenomenon was not observed with a mechanical dissociation at 4°C (Bennett et al., 2016).”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Bennett et al., 2016
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
“Research has also shown that the enzymatic dissociation of brain tissue at 37°C results in an upregulation of inflammatory genes in microglia.”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Bennett et al., 2016
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
“All three of these cytokines are highly expressed specifically by microglia13,15, again suggesting a critical role for microglia in inducing A1 reactive astrocytes.”
From Neurotoxic reactive astrocytes are induced by activated microglia (2017) · cites this paper as [15]
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
“TMEM119 is a cell surface protein and a specific marker for microglial subpopulations in bone marrow and neural cells [37].”
From miR-223 accelerates lipid droplets clearance in microglia following spinal cord injury by upregulating ABCA1 (2024) · cites this paper as [37]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Mature pMGLs stained positive for markers of murine and human microglia 10,11,29,30, with both TMEM119 and P2RY12 displaying a broad membrane and punctate vesicular expression pattern”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“However, generation of microglia-like cells matching the recently identified signatures of acutely isolated microglia 10,11, and following their non-monocytic yolk sac ontogeny 4, has not been reported from pluripotent human cells.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“TMEM119 has been shown to be stably and specifically expressed in microglia [41,44], and it can be used to distinguish microglia from resident and infiltrating macrophages [41].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [41]
The cited source says what the claim attributes to it.
In the citing paper
“while rodent studies even demonstrated an expression of 98% of CD45lowCD11b+ cells in adult animals [41].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [41]
The cited source says what the claim attributes to it.
In the citing paper
“we performed in situ RNA labeling for TMEM119, a canonical microglia marker not expressed by other CNS resident macrophages (Bennett et al. 2016).”
From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Bennett et al. 2016
The cited source says what the claim attributes to it.
In the citing paper
“we co-stained for CD11b and for the transmembrane protein 119 (Tmem119), a microglia specific marker (M. L. Bennett et al., 2016).”
From Activated microglia drive demyelination via CSF1R signaling (2021) · cites this paper as M. L. Bennett et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“We thereby identified a low but significant number of donor-derived immune cells that were Tmem119+, indicating that they had adopted a microglia-like phenotype35 (Figure 2E).”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [35]
The cited source says what the claim attributes to it.
In the citing paper
“As a set, genes previously identified to be associated specifically with microglia but not with blood monocytes (Bennett et al., 2016, Butovsky et al., 2014, Melief et al., 2012) (Figure 2C) showed similar expression in co-pMG and fetalMG.”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Bennett et al., 2016
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Further, SPI1, MS4A4A, MS4A6A, and SELL are specifically expressed in microglia based on RNA-Seq data29–31”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [30]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Animal microglia are often inaccessible to real-time imaging, and cannot fully reflect human biology.15–17”
From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [15]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“WAVE2 is expressed at high levels in microglia and vascular endothelial cells14,15.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [15]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Mcm5, an established regulator of microglial cell cycle that is strongly expressed during embryonic and early postnatal microglial development”
From Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system (2023) · cites this paper as [38]
Experimental — accuracy not yet measuredIn the citing paper
“Several of these microglial genes were also observed in human microglia, including P2RY12 and TMEM119 (REFs25,33–36).”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [35]
In the citing paper
“microglia express lower levels of receptor-type tyrosine-protein phosphatase C (PTPRC; also known as CD45) than monocytes, allowing these two cell types to be discriminated, whereas the expression of scavenger receptor cysteine-rich type 1 protein M130 (CD163) by microglia enables their distinction from perivascular macrophages35,44–47.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [35]
In the citing paper
“Within these three AD modules, we observed enrichment of pro-inflammatory genes in the Magenta module (Ptgs2, Il12b, Tlr2, Hif1a, Cd69, Il1b, Cxcl16 and Irg1) and anti-inflammatory and phagocytic genes in the Yellow module (Igf1, Dpp7, Apoe, Spp1, Cd200r4 and Lpl) [38] while the Blue module contained several homeostatic microglial genes (Tmem119, P2ry12, Mtss1 and Tgfbr1, Fig. 2d) [39].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [39]
In the citing 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).”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Bennett et al., 2016
In the citing paper
“We used a recently developed protocol for cell extraction to minimize microglial activation (Bennett et al., 2016).”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Bennett et al., 2016
In the citing paper
“Barres group recently identified Tmem119++/Sall1+/Gpr56+/Apoe+ as yolk sac-derived microglia, whereas hematopoietic stem cell-derived microglia-like cells express Tmem119+/Ms4a7+/Clec12a+/Apoe+++ suggesting lineage-specific microglia markers that can be useful in determining the origin of microglia [18, 19].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [19]
In the citing paper
“suggesting lineage-specific microglia markers that can be useful in determining the origin of microglia [18, 19].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [19]
In the citing paper
“Barres group recently identified Tmem119++/Sall1+/Gpr56+/Apoe+ as yolk sac-derived microglia, whereas hematopoietic stem cell-derived microglia-like cells express Tmem119+/Ms4a7+/Clec12a+/Apoe+++ suggesting lineage-specific microglia markers that can be useful in determining the origin of microglia [18, 19].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [19]
In the citing paper
“Recent genomic and proteomic studies revealed microglia express a unique set of genes distinct from infiltrating monocytes and other immune cells [18, 19].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [19]
In the citing paper
“In the mouse, several microglia-specific genes appear to be upregulated in brain-resident microglia through early postnatal development 10.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [10]
In the citing paper
“Cx3cr1+ perivascular/meningeal macrophages were identified by low Tmem119, low Hexb, and high Mrc1 expression35,84 and excluded from single cell analysis (n=1-5 per plate).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [84]
In the citing paper
“The addition of CD200 and CX3CL1 to iMGLs increased the expression of select genes like COMT (Bennett et al., 2016)(Figure S5B), CD52, a cell surface receptor that binds Siglec-10 and interacts with DAP12 as part of the microglia sensome (Hickman et al., 2013) and HLADRB5, a member of the MHC II complex implicated in AD, while maintaining similar expression levels of core-microglial genes (e.g. P2”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Bennett et al., 2016
In the citing paper
“We observed that over 90% of CD11b+ cells in brains from the 5xFAD Rubicon+/− and−/− mice were TMEM119+ (a microglia-specific marker (Bennett et al., 2016)) (Fig. S5C,D). Furthermore, the TMEM119+ cells isolated from 5xFAD Rubicon−/− mice had higher Iba1 expression compared to Rubicon+/− animals (Fig. S5E).”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Bennett et al., 2016
In the citing paper
“In particular, the identification of the transmembrane protein TMEM119 as a specific marker of microglia has enabled global gene expression profiling of highly pure preparations of microglia (9).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [9]
In the citing paper
“We analyzed TMEM119 in bulk human brain tissue data from the Allen Brain Institute (13) because it is a highly specific and well-validated marker of brain-derived microglia in both mice and humans.”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [9]
In the citing paper
“and appears to exhibit stable expression even in response to a variety of inflammatory conditions (9, 96).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [9]
In the citing paper
“Secondly, we utilized TMEM119 as a marker of microglial expression, which was shown in 2016 to be a highly specific marker of brain-derived microglia (9).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [9]
In the citing paper
“TMEM119 has been shown to be stably and selectively expressed in adult microglia (9, 95)”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [9]
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Citations
Cites
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
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Trapnell, C., Roberts, A., Goff, L. A., Pertea, G. M., Kim, D., Kelley, D. R., Pimentel, H., Salzberg, S. L., Rinn, J. L., & Pachter, L. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.016 · Cited by 12,145
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827
Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 2×
“We calculated percentile ranks for several canonical activation genes for our naïve and LPS-stimulated samples, as well as five published datasets (15, 17, 30, 33, 34); these datasets were generated using CD45 or Cx3cr1 rather than a specific microglia marker, such as Tmem119, and used enzymatic digestion or Percoll f…”
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Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · cited 1×
“Given the recently identified novel role for the complement cascade and microglia in synaptic phagocytosis in normal development and disease (48), we compared expression of relevant genes in microglia and CNS macrophages.”
BackgroundSelf-citationATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913
Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis
Yona, S., Kim, K.-W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Viukov, S., Guilliams, M., Misharin, A., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.12.001 · Cited by 3,245
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
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Metadata
- Authors
- Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., Weissman, I. L., Chang, E. F., Li, G., Grant, G. A., Hayden Gephart, M. G., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- The University of Melbourne (AU)
- University of California, San Francisco (US)
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-02-16
- Volume
- 113
- Issue
- 12
- Pages
- E1738-46
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4812770
- OpenAlex
- W2280077905
- Cited by
- 1,804
- References
- 58
- Citations by year
- 2026: 98 · 2025: 122 · 2024: 175 · 2023: 184 · 2022: 241 · 2021: 251 · 2020: 228 · 2019: 189 · 2018: 174 · 2017: 110 · 2016: 30
- FWCI
- 91.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Child Health and Human Development (F31NS078813, R21HD075359)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R47DA15043, 5K08NS075144-05)
- HHS | NIH | National Institute of Mental Health (5T32MH019938-22)
- HHS | NIH | National Cancer Institute (F32HL115973-02)
- Department of Health, Australian Government | National Health and Medical Research Council (GNT1052961)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Keywords
- microglia, TMEM119, monoclonal antibodies, microglia isolation, microglial development, postnatal maturation, microglial transcriptome, central nervous system injury, brain development, myeloid cells, neuroinflammation
- MeSH terms
- Aged, Animals, Antibodies, Monoclonal, Brain, Cell Division, Child, Humans, Lipopolysaccharides, Macrophages, Membrane Proteins, Middle Aged, Nerve Crush, Nerve Tissue Proteins, Organ Specificity, Rabbits, Sciatic Nerve, Temporal Lobe, Biomarkers, Sequence Analysis, RNA, Microglia, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Lineage, Endotoxemia, Optic Nerve Injuries, Gene Expression Profiling, Mice, Transcriptome
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