The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
Microglia development follows a stepwise program to regulate brain homeostasis
Abstract
Microglia development follows a stepwise program: Microglia are cells that defend the central nervous system. However, because they migrate into the brain during development, the changes that they undergo, including those that affect gene expression, have been difficult to document. Matcovitch-Natan et al. transcriptionally profiled gene expression and analyzed epigenetic signatures of microglia at the single-cell level in the early postnatal life of mice. They identified three stages of microglia development, which are characterized by gene expression and linked with chromatin changes, occurring in sync with the developing brain. Furthermore, they showed that the proper development of microglia is affected by the microbiome. Science , this issue p. 789
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In the citing paper
“Gene expression studies have shown that microglial cells have distinct profiles during the embryonic, early post-natal, and adult stages (26).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [26]
In the citing paper
“MAFB is known to play a key role in the final stages of microglial development from yolk sac progenitors, supporting the acquisition and maintenance of microglial identity (19).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [19]
In the citing paper
“Additionally, it promotes the final stages of microglial development from yolk sac progenitors, facilitating the acquisition and maintenance of microglia identity (19).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [19]
In the citing paper
“Integration of these findings with recent studies of yolk sac and embryonic microglia (56, 63) suggests a model by which intersecting developmentally determined and environment-dependent transcriptional networks establish microglia identity and function (Fig. 6E).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [63]
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 [21]
In the citing paper
“To minimize the reported effect of brain region on microglial gene expression 6,23,24 , only cortical microglia were included in our comparisons.”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [24]
In the citing paper
“An extensive overlap was observed between human and these three independent mouse microglial gene expression data sets ( Fig. 2c ). The median ∆ percentiles were 14.3, 20.4 and 9.3 for our own expression data set, that of Grabert et al. 23 and that of Matcovich-Natan et al. 24 , respectively.”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [24]
In the citing paper
“Microglia from adult GF mice also display differential expression of genes associated with microglial maturation, including down-regulation of genes that regulate cell activation and immune system defense pathways, such as Mapk8, IL-1α, Ly86, Jak3, and Stat1, all of which are normally highly expressed in adult microglia (Fig. 1; Erny et al., 2015; Matcovitch-Natan et al., 2016).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“However, the differences in the microglial transcriptome seen in offspring from MIA versus healthy dams decline as mice reach adulthood.”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“Microglia from young MIA offspring show increased expression of inflammation-related genes typically associated with an adult microglial phenotype and down-regulation of genes expressed during earlier developmental stages (e.g., Pu.1 and Irf8), suggesting that maternal inflammation disrupts the timeline of normal microglial maturation (Matcovitch-Natan et al., 2016).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“While commensal symbiotic bacteria are critical for proper microglial maturation, induction of infection in pregnant dams can have disruptive effects on the progression of microglial development in offspring (Pratt et al., 2013; Matcovitch-Natan et al., 2016; Mattei et al., 2017).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“We found that microglial diversity is highest during early development, when microglia are still differentiating (Matcovitch-Natan et al., 2016).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“These signatures - cell cycle, phagocytosis, and surveillance - correspond with only three of the nine states presented here (Matcovitch-Natan et al., 2016).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“our new cluster definitions highlight the greater degree of developmental complexity that were covered up by dominating signatures in bulk sequencing experiments.”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“This study uses single-cell RNA-sequencing and bioinformatics to describe microglial transcriptome profiles and temporal stages of development in early, pre-adult microglia, which are regulated by distinct regulatory circuits.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [82]
In the citing paper
“GF mice display marked defects in microglia structure and function and hence feature impaired CNS innate immune responses.240,241”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [241]
In the citing paper
“our study detected about 3 times as many genes per cell, and produced higher detection rates for over 80% of genes”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“which consists of three distinct temporal stages: early microglia spanning until embryonic day 14, premicroglia from embryonic day 14 to a few weeks after birth, and adult microglia from a few weeks after birth onward [13].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [13]
In the citing paper
“In mice, microglia undergo a step-wise program of maturation that is synchronized with the developmental phases of the brain [13, 14]”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [13]
In the citing paper
“ATAC-seq of isolated microglia across different developmental stages showed that accessibility of promoter regions by transcriptional complexes was largely conserved over time [13, 34].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [13]
In the citing paper
“Hippocampal microglial cells from polyI:C offspring mice showed dysregulation of genes associated with inflammatory response, cell migration and phagocytosis [13, 59, 60].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [13]
In the citing paper
“Maternal immune activation (MIA) by administration of polyinosinic:polycytidylic acid (polyI:C), which is a synthetic analog of double-stranded RNA used to simulate viral infections via interaction with TLRs, can disrupt pre-microglial development in offspring, leading to a more advanced developmental stage.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [13]
In the citing paper
“showing dramatic differences in microglial gene expression between early postnatal periods (P3–9) and adulthood (2 months) (Matcovitch-Natan et al., 2016).”
From Local cues establish and maintain region-specific phenotypes of basal ganglia microglia (2017) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“The cerebellar microglia phenotype is reminiscent of microglia during early brain development9,10 as well as microglia associated with neurodegenerative disease11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [10]
In the citing paper
“Furthermore, cbMg show an increase in the expression of genes characteristic of immature microglia9,10, as well as genes that are expressed in neurodegenerative disease-associated microglia (such as primed microglia, MGnD, and DAMs)11–13 (Supplementary Fig. 5c,d, Supplementary Table 4).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [10]
In the citing paper
“We found that the cbMg-specific clearance gene expression pattern significantly overlaps with the signature of microglia associated with neurodegeneration11–13 and early brain development9,10, two stages of life characterized by enhanced neuronal attrition and heightened microglia clearance activity.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [10]
In the citing paper
“This is another key characteristic feature of early microglia progenitors9,10 as well as microglia exposed to dying neurons during different diseases11–13.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [10]
In the citing paper
“iMGLs not cultured with neurons differentially expressed early microglia genes including FFAR2”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Matcovitch-Natan et al., 2016
In the citing paper
“Another study with germ-free mice found functional defects in microglia and as a result observed heightened levels of proinflammatory cytokines IL-1B, IL-6, and TNF-alpha [39], indicating an impairment in immune function.”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [39]
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InfluentialTranscription factors that define the epigenome structures and transcriptomes in microglia
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“Interestingly, fetal microglia only encounters minor transcriptional changes in the absence of microbiota, whereas the effects become more pronounced in early postnatal and adult microglia (18, 41).”
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“MIA induced by PolyI:C has a transcriptional and functional impact on embryonic microglia, transiently upregulating genes associated with proinflammatory and IFN-b responses [66,75,76], while downregulating genes involved in proliferation [66].”
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BackgroundForward programming human pluripotent stem cells into microglia
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“5-P9 [21].”
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Metadata
- Authors
- Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., Keren-Shaul, H., Gury, M., Lara-Astaiso, D., Thaiss, C. A., Cohen, M., Bahar Halpern, K., Baruch, K., Deczkowska, A., Lorenzo-Vivas, E., Itzkovitz, S., Elinav, E., Sieweke, M. H., Schwartz, M., & Amit, I.
- Affiliations
- Weizmann Institute of Science (IL)
- Centre d'Immunologie de Marseille-Luminy (CIML), Université Aix-Marseille, UM2, Campus de Luminy, Marseille, France.
- Centre National de la Recherche Scientifique (FR)
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
- Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
- Corresponding author
- Matcovitch-Natan, Orit
- Winter, Deborah R.
- Sieweke, Michael H.
- Schwartz, Michal
- Amit, Ido
- ORCID
- Venue
- Science
- Published
- 2016-08-19
- Volume
- 353
- Issue
- 6301
- Pages
- aad8670-aad8670
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2468501494
- Cited by
- 1,180
- References
- 82
- Citations by year
- 2026: 76 · 2025: 111 · 2024: 119 · 2023: 105 · 2022: 144 · 2021: 145 · 2020: 143 · 2019: 117 · 2018: 119 · 2017: 84 · 2016: 17
- FWCI
- 61.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- European Research Council (309788)
- Israeli Science Foundation (1782/11)
- European Commission Seventh Framework Programme (EC FP7)
- Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine
- Minerva Stiftung
- Israeli Ministry of Science, Technology and Space
- David and Fela Shapell Family Foundation
- National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193)
- Alan and Laraine Fischer Career Development Chair
- Advanced European Research Council (232835)
- EC FP7 HEALTH-2011 (279017)
- Agence Nationale de la Recherche (ANR BLAN07-1_205752, ANR-11-BSV3-026-01)
- Fondation pour la Recherche Medicale (20071210559, 20110421320)
- InCA (13-10/405/AB-LC-HS)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- microglia development, brain homeostasis, MAFB, chromatin regulation, single-cell transcriptomics, microbiome, prenatal immune activation, neurodevelopmental disorders, immune pathways, myeloid cells
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Chromatin, Female, Homeostasis, Immunity, Mice, Inbred C57BL, Microglia, Mice, Knockout, Gene Expression Profiling, Myeloid Cells, Histone Code, Epigenesis, Genetic, MafB Transcription Factor, Mice, Neurogenesis, Gene Knockout Techniques, Single-Cell Analysis
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