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Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
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Primitive Origins for Microglia: Microglia are the resident macrophages of the central nervous system and are associated with neurodegeneration and brain inflammatory diseases. Although the developmental origins of other tissue macrophage populations are well established, the origins of microglia remain controversial. Ginhoux et al. (p. 841 , published online 21 October) used in vivo lineage tracing studies to show that microglia arise early in mouse development and derive from primitive macrophages in the yolk sac. This is in contrast to other cells of the mononuclear phagocyte system, which arise later in development from a distinct progenitor population.
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“Two weeks after injection, CSF1R knockout brains had been partially repopulated with CD11b+ CD45+ cells (Fig. S7B), which are absent from non-engrafted brains (Ginhoux et al., 2010).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Ginhoux et al., 2010
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.
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“Importantly, microglia originate from the yolk sac during early embryonic development, whereas peripheral macrophages originate from hematopoietic stem cells in the bone marrow (19).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [19]
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
“microglia are uniformly CX3CR1+ from early embryonic time points through adulthood (Cardona et al., 2006; Ginhoux et al., 2010; Schulz et al., 2012)”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Ginhoux et al., 2010
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.
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“It is believed that microglia arise from yolk sac erythromyeloid precursors and migrate into the brain parenchyma during early development [43,44,45].”
From The Cuprizone Model: Dos and Do Nots (2020) · cites this paper as [44]
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.
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“Microglia share much of their genetic make-up, complement of proteins, and function, with other immune cells, particularly macrophages [129]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [129]
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“aging, vascular dysfunction, and chronic neuroinflammation are known to compromise the integrity of the blood–brain barrier. This can lead to increased trafficking of peripheral immune cells as well as the above-mentioned microglial replacement of resident microglia by peripheral monocytes [24,36].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [36]
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
“Microglia originate from primitive macrophage (M F ) progenitors that arise in the yolk sac (YS), infiltrate the developing brain and clonally expand 2,3 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [2]
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“In mice, two waves of embryonic macrophages are produced in the yolk sac blood islands at embryonic day 7.5 (E7.5) and E8.25, and the first wave migrate into the developing brain and differentiate to microglia (Ginhoux et al., 2010, Gomez Perdiguero et al., 2015, Hoeffel et al., 2015, Palis et al., 1999).”
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 Ginhoux et al., 2010
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In the citing paper
“This lineage is mainly regulated by CSFR14 and its ligand, IL-347.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [4]
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
“Our findings are consistent with reports that macrophage progenitors develop from the primitive ectoderm of the yolk sac4 and give rise to tissue macrophages that do not have a monocytic progenitor16,17.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [4]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“To provide this niche, we used CSF1R knockout animals, which lack microglia (Ginhoux et al., 2010) (schematic in Fig. 7A).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Ginhoux et al., 2010
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In the citing paper
“In mice, fate-mapping methods revealed that, unlike other glia cells with neuroectoderm origin, microglia in adults originate from yolk-sac (YS)-derived primitive macrophages, which colonize the developing brain rudiment during early embryogenesis (Ginhoux et al., 2010; Schulz et al., 2012).”
From Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals (2025) · cites this paper as Ginhoux et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“Microglia are the primary resident immune cells of the CNS parenchyma and are seeded during development from mesodermal progenitors”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Ginhoux et al., 2010
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In the citing paper
“These cells arise from uncommitted KIT+ erythromyeloid precursors [181, 316], which seed the brain from the yolk sac at embryonic day 9.5 in the mouse [126], well before other glial cells and the formation of the blood–brain barrier (BBB) [130, 181].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [126]
The cited source says what the claim attributes to it.
In the citing paper
“Microglia and monocytes are ontogenetically distinct: microglia derive from yolk-sac progenitors during embryogenesis (Ginhoux et al., 2010; Schulz et al., 2012)”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Ginhoux et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“In addition, IL-34 is newly identified ligand for CSF-1R, and it is reported to support maintenance of microglia [14].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [14]
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In the citing paper
“Peripheral immune cells may also replace microglial populations,5,23,30–32 though this is controversial.”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“Studies in mice indicate that microglia are derived from yolk sac progenitor cells that populate the brain early in development (18, 19).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [18]
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In the citing paper
“Our own work (Buchrieser et al., 2017) and that of others (Hoeffel et al., 2015) indicates that this protocol produces MYB-independent myeloid cells, recapitulating an embryonic ontogeny, and lineage-tracking studies in mouse have demonstrated that microglia derive from primitive, yolk sac macrophages that migrate into the developing brain (Ginhoux et al., 2010, Ginhoux et al., 2013).”
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 Ginhoux et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“adult microglia derive from primitive macrophages4 in a Myb-independent manner5 via PU.1 and IRF8 dependent pathways6.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Thus, there is a resident pool of microglia that is separate from peripheral myeloid cells that infiltrate the nervous system.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Subsequent reports showed that microglia arise early during development from progenitors in the embryonic yolk sac4,38,39.”
From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [4]
In the citing paper
“Bone marrow–derived myeloid precursors do not contribute to the microglia pool.”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [1]
In the citing paper
“Fate-mapping studies have demonstrated that microglia originate from early myeloid progenitors in the embryonic yolk sac that migrate into the developing neural tube, where they proliferate, colonize the entire parenchyma, and subsist throughout the life span of the organism by slow division (1, 2).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [1]
In the citing paper
“Normal blood circulation is required for YS macrophage seeding of the CNS.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [42]
In the citing paper
“This observation supports the idea that the recruitment of YS progenitors into the brain is mediated by blood circulation.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [42]
In the citing paper
“it is now well-established that microglia are derived from yolk sac (YS) erythromyeloid precursors (EMPs).”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [42]
In the citing paper
“The origin of microglia has now been clearly defined and shown to relate to the early colonization of the CNS by mesodermal progenitors6 that arise from the yolk sac7,8”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [8]
In the citing paper
“the cytokine CSF1, acting via its receptor CSF1R, is important for microglial development8.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [8]
In the citing paper
“Microglia arise from yolk sac-derived precursors that populate the brain during early development21.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [21]
In the citing paper
“Several groups have attempted different cell culture conditions to maintain homeostatic microglia signature and ramified morphology In vitro using a variety of cytokines, such as CSF1, GM-CSF, TGFβ, and IL-34 [73-76].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [73]
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 [4]
In the citing paper
“They emigrate as erythromyeloid precursors or primitive macrophages from the yolk sac, before further hematopoiesis takes place in the periphery.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [4]
In the citing paper
“recent genetic lineage tracing in the mouse determined that microglia take up residence in the developing neural tube shortly before closure of the blood-brain barrier 4.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [4]
In the citing paper
“Elegant lineage tracing studies show that microglia originate from yolk sac erythromyeloid progenitors (EMP) generated during primitive hematopoiesis (Ginhoux et al., 2010; Kierdorf et al., 2013; Schulz et al., 2012).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Ginhoux et al., 2010
In the citing paper
“We identified eleven TFs upregulated in PS19 mice that are implicated in mediating the inflammatory responses (Stat1, Stat3, Stat5a, Stat5b, Nfkb1, Nfe2l2, Fli1), microglia proliferation and differentiation (Irf8, Spi1, Runx1), and astrocyte maturation and neurogenesis (Pax6) (Ginhoux et al., 2010; Kierdorf et al., 2013; Zamanian et al., 2012; Zusso et al., 2012).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Ginhoux et al., 2010
In the citing paper
“They are derived from embryonic yolk sac (YS) precursors and maintain their CNS population via local self-renewal, with little contribution from bone marrow-derived monocytes12,13.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [12]
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Metadata
- Authors
- Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., Samokhvalov, I. M., & Merad, M.
- Affiliations
- Singapore Immunology Network (SG)
- Icahn School of Medicine at Mount Sinai (US)
- Department of Gene and Cell Medicine and the Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.
- Albert Einstein College of Medicine (US)
- Institute for Brain Disorders and Neural Regeneration, Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, and Department of Neurology, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
- Indiana University Indianapolis (US)
- RIKEN (JP)
- Corresponding author
- Ginhoux, Florent
- ORCID
- Venue
- Science
- Published
- 2010-11-05
- Volume
- 330
- Issue
- 6005
- Pages
- 841-845
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3719181
- OpenAlex
- W2148898943
- Cited by
- 5,175
- References
- 32
- Citations by year
- 2026: 286 · 2025: 360 · 2024: 447 · 2023: 369 · 2022: 443 · 2021: 483 · 2020: 425 · 2019: 382 · 2018: 363 · 2017: 328 · 2016: 279 · 2015: 279 · 2014: 271 · 2013: 219 · 2012: 137
- FWCI
- 87.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health (CA26504)
- RIKEN
- National Heart, Lung, and Blood Institute (HL086899, R01HL086899, R01HL060714)
- National Institute of Mental Health (R01MH066290, MH66290)
- National Cancer Institute (CA-32551, R01CA032551, R37CA026504, R01CA112100, CA26504, CA112100, R01CA026504)
- National Institute of Allergy and Infectious Diseases (AI080884, R01AI080884)
- National Institute of Neurological Disorders and Stroke (NS38902, R01NS038902)
- 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
- myeloid progenitor cells, CSF-1, CSF-1 receptor, reticuloendothelial system, hematopoietic progenitor cells, lineage tracing, neuroinflammation, neurodegenerative diseases
- MeSH terms
- Animals, Brain, Cell Differentiation, Embryo, Mammalian, Female, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Macrophages, Mice, Inbred C57BL, Yolk Sac, Macrophage Colony-Stimulating Factor, Receptor, Macrophage Colony-Stimulating Factor, Microglia, Cell Lineage, Myeloid Progenitor Cells, Cell Proliferation, Core Binding Factor Alpha 2 Subunit, Mice, Gene Knock-In Techniques
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