The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease
Open accessAbstract
The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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
“Moreover, the somatic BRAF p.V600E variant, a common cancer driver variant, in the microglial lineage has been causally implicated not in cancer, but instead in degeneration of neurons secondary to clonal expansion and activation of mutant microglia in both mouse models and humans29.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [29]
Experimental — accuracy not yet measuredIn the citing paper
“a recent study using transgenic mice showed that microglial proliferation and activation induced by a BRAF mutation restricted to erythromyeloid progenitors could drive late-onset neurodegeneration (Mass et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Mass et al., 2017
In the citing paper
“microglia from the mutant mice as well as from brain tissue of patients with BRAF mutation–associated neurodegenerative disease showed increased inflammatory cytokine expression (Mass et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Mass et al., 2017
In the citing paper
“Importantly, microglia proliferation preceded neuron loss, and microglia from the mutant mice as well as from brain tissue of patients with BRAF mutation–associated neurodegenerative disease showed increased inflammatory cytokine expression (Mass et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Mass et al., 2017
In the citing paper
“Exacerbated activation of microglia has been shown to promote microglia-mediated neuronal attrition7,8.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [7]
In the citing paper
“The ability of aberrant intrinsically activated microglia to cause neuronal damage is further supported by recent findings showing that cell-autonomous activation of the RAF–MEK–ERK pathway in microglia leads to the loss of synapses and the development of a severe late-onset neurodegenerative disorder7.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [7]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · cited 1×
“FASTQ files were mapped to the Mouse genome mm10 using the Star aligner 37 that maps reads gnomically and resolves reads across splice junctions.”
clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters
Yu, G., Wang, L.-G., Han, Y., & He, Q.-Y. (2012) · OMICS: A Journal of Integrative Biology · doi:10.1089/omi.2011.0118 · Cited by 36,259 · cited 1×
“Gene set enrichment analysis on KEGG pathway, GO term, Reactome, and MSigDB gene set collection was done using the over-representation test with hypergeometric model to assess whether the number of selected genes associated with disease is larger than expected 40 .”
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343
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
CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis
Qian, B.-Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L. R., Kaiser, E. A., Snyder, L. A., & Pollard, J. W. (2011) · Nature · doi:10.1038/nature10138 · Cited by 2,874 · cited 2×
“We achieved somatic mosaicism for a BRAF V600E allele 26 and yellow fluorescent protein (YFP) in the resident macrophage lineage using inducible genetic targeting 20,22,23 in Csf1r MerCreMer mice 27 (Fig.”
A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells
Schulz, C., Perdiguero, E. G., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W., et al. (2012) · Science · doi:10.1126/science.1219179 · Cited by 2,578 · cited 15×
“For flow cytometry experiments, organs were incubated in PBS containing 1mg/ml collagenase D (Roche), 100U/ml DNase I (Sigma), 2.4mg/ml of dispase (Invitrogen) and 3% FCS (Invitrogen) at 37°C for 30 min prior to mechanical disruption.”
InfluentialSelf-citationVariant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors
Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., Garner, H., Trouillet, C., de Bruijn, M. F., Geissmann, F., et al. (2015) · Nature · doi:10.1038/nature13989 · Cited by 2,339
Self-citationHow neuroinflammation contributes to neurodegeneration
Ransohoff, R. M. (2016) · Science · doi:10.1126/science.aag2590 · Cited by 1,967
Cited by
Sorted by citations
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
“Late-onset AD appears to result mainly from a mixture of genetic and environmental factors, including aging, that impair the brain’s ability to clear Aβ (Mawuenyega et al., 2010; Wildsmith et al., 2013).”
BackgroundMicroglia Biology: One Century of Evolving Concepts
Prinz, M., Jung, S., & Priller, J. (2019) · Cell · doi:10.1016/j.cell.2019.08.053 · Cited by 1,525
Self-citationMicroglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation
Prinz, M., Masuda, T., Wheeler, M. A., & Quintana, F. J. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-093019-110159 · Cited by 584
Self-citationAllen, C. E., Mérad, M., & McClain, K. L. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1607548 · Cited by 579
“from the fetal yolk sac to drive neurodegeneration.(29)”
Co-option of Neutrophil Fates by Tissue Environments
Ballesteros, I., Rubio-Ponce, A., Genua, M., Lusito, E., Kwok, I., Calvo, G. F., Khoyratty, T. E., van Grinsven, E., González-Hernández, S., Nicolás-Ávila, J. Á., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.003 · Cited by 506
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
Wang, S., Sudan, R., Peng, V., Zhou, Y., Du, S., Yuede, C. M., Lei, T., Hou, J., Cai, Z., Cella, M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.033 · Cited by 471
Epigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460
Microglia and early brain development: An intimate journey
Thion, M. S., Ginhoux, F., & Garel, S. (2018) · Science · doi:10.1126/science.aat0474 · Cited by 461
Immune cell regulation of glia during CNS injury and disease
Greenhalgh, A. D., David, S., & Bennett, F. C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0263-9 · Cited by 409
Galindo, C. R., & Allen, C. E. (2020) · Blood · doi:10.1182/blood.2019000934 · Cited by 377
Microglia, Lifestyle Stress, and Neurodegeneration
Madore, C., Yin, Z., Leibowitz, J. A., & Butovsky, O. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.003 · Cited by 313
“Indeed, somatic mutations in the lineage of erythro-myeloid progenitors (EMPs), to which microglia belong, might drive lateonset neurodegeneration by leading to constant microglial nuclear factor κB (NF-κB) activation and resulting in neuronal loss (Mass et al., 2017).”
BackgroundThe identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308
Macrophages of distinct origins contribute to tumor development in the lung
Loyher, P.-L., Hamon, P., Laviron, M., Meghraoui, A., Gonçalves, E., Deng, Z., Torstensson, S., Bercovici, N., de Chanville, C. B., Combadière, B., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20180534 · Cited by 305
Self-citationTwo to Tango: Dialog between Immunity and Stem Cells in Health and Disease
Naik, S., Larsen, S. B., Cowley, C. J., & Fuchs, E. V. (2018) · Cell · doi:10.1016/j.cell.2018.08.071 · Cited by 246
“In this regard, there are three obvious means of leveraging these interactions for therapeutic benefit: (1) boosting immune mediators to promote regeneration, (2) correcting immune abnormalities that underlie tissue degeneration, and (3) interrupting this dialog to curb pathologies in autoimmune conditions and aging (…”
BackgroundActivating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms
Durham, B. H., Lopez-Rodrigo, E., Picarsic, J. L., Abramson, D. H., Rotemberg, V. M., Munck, S. D., Pannecoucke, E., Lu, S. X., Pastore, A., Yoshimi, A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0653-6 · Cited by 231
“Targeted RNA sequencing was also used for the purposes of detecting gene fusions using the MSK-Fusion targeted RNA-seq assay.”
Self-citationMicroglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan
Tay, T. L., Béchade, C., D’Andrea, I., St‐Pierre, M., Henry, M. S., Roumier, A., & Tremblay, M. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00421 · Cited by 217
“Notably, a somatic mutation in the erythromyeloid progenitor of microglia was shown to cause neurodegenerative disease in mouse and human (Mass et al., 2017).”
BackgroundIntersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197
The Myeloid Cell Compartment—Cell by Cell
Bassler, K. E., Schulte-Schrepping, J., Warnat‐Herresthal, S., Aschenbrenner, A. C., & Schultze, J. L. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041728 · Cited by 200
Microglia as Dynamic Cellular Mediators of Brain Function
Wright-Jin, E. C., & Gutmann, D. H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.08.013 · Cited by 195
“Since the myeloid cells that cause this tissue macrophage disorder share a similar yolk sac progenitor as microglia, BRAF-mediated ERK hyperactivation in resident brain microglia partly underlie the pathogenesis of this progressive neurodegenerative condition [22].”
BackgroundPolyphenols as Potential Metal Chelation Compounds Against Alzheimer’s Disease
Lakey‐Beitia, J., Burillo, A., Penna, G. L., Hegde, M. L., & Rao, K. S. J. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200185 · Cited by 190
“The etiology of NDDs is closely related to aging, but other factors are also involved, such as genomic instability, de novo and somatic mutations, epigenetic alterations, and environmental factors that include stressful situations, infections, and poor nutrition [4, 14].”
Origins, Biology, and Diseases of Tissue Macrophages
Cox, N., Pokrovskii, M. V., Vicario, R., & Geissmann, F. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-093019-111748 · Cited by 169
Self-citationMcClain, K. L., Bigenwald, C., Collin, M. P., Haroche, J., Marsh, R. A., Mérad, M., Picarsic, J. L., Ribeiro, K. B., & Allen, C. E. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00307-9 · Cited by 163
Analyzing microglial phenotypes across neuropathologies: a practical guide
Schwabenland, M., Brück, W., Priller, J., Stadelmann, C., Lassmann, H., & Prinz, M. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02370-8 · Cited by 149
Self-citationMicroglia: Key players in neurodevelopment and neuronal plasticity
Sominsky, L., Luca, S. N. D., & Spencer, S. J. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.11.012 · Cited by 155
An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains
Millet, A., Ledo, J. H., & Tavazoie, S. F. (2024) · Immunity · doi:10.1016/j.immuni.2023.12.001 · Cited by 132
Emile, J., Aubart, F. C., Collin, M. P., Fraitag, S., Idbaïh, A., Abdel-Wahab, O. I., Rollins, B. J., Donadieu, J., & Haroche, J. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00311-1 · Cited by 138
Self-citationMcClain, K. L., Picarsic, J. L., Chakraborty, R., Zinn, D., Lin, H., Abhyankar, H. A., Scull, B., Shih, A., Lim, K. P. H., Eckstein, O. S., et al. (2018) · Cancer · doi:10.1002/cncr.31348 · Cited by 137
“The activated BRAFV600E1 myeloid/monocytic cells are associated with regional parenchymal white matter injury, gliosis and demyelination and a leukoencephalopathic pattern of neurodegeneration along with infiltrating lymphocytes as described previously.8,13,14,37 Common origins of monocyte-derived inflammatory microgl…”
BackgroundResultInfluentialThe influence of environment and origin on brain resident macrophages and implications for therapy
Bennett, M. L., & Bennett, F. C. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0545-6 · Cited by 135
Macrophages and Cardiovascular Health
Frodermann, V., & Nahrendorf, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00068.2017 · Cited by 128
Il34-Csf1r Pathway Regulates the Migration and Colonization of Microglial Precursors
Wu, S., Xue, R., Hassan, S., Nguyen, T. M. L., Wang, T., Pan, H., Xu, J., Liu, Q., Zhang, W., & Wen, Z. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.08.005 · Cited by 122
Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes
Lee, W., Lee, H.-S., Kim, D.-Y., Lee, H., Moon, J., Park, K., Lee, S. K., Chu, K., & Lee, S. (2022) · Brain · doi:10.1093/brain/awac166 · Cited by 126
Microglia in neurodegenerative diseases
Xu, Y., Jin, M.-Z., Yang, Z., & Jin, M.-Z. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.290881 · Cited by 121
“A BRAF inhibitor prevents the phosphorylation of extracellularly regulated protein kinases and reduces microglia accumulation and astrogliosis, phagocytosis, demyelination, neuronal loss, and APP deposits (Mass et al., 2017).”
BackgroundFerrero, G., Mahony, C. B., Dupuis, E., Yvernogeau, L., Ruggiero, E. D., Miserocchi, M., Caron, M., Robin, C., Traver, D. J., Bertrand, J. Y., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.066 · Cited by 124
“While it was generally believed that MG do not contribute directly to CNS pathologies, increasing evidence now indicates that defectiveMGcanbedirectly causative in several neurological disorders (Guerreiro et al., 2013; Mass et al., 2017; Paloneva et al., 2002; Rademakers et al., 2011).”
BackgroundEckstein, O. S., Visser, J., Galindo, C. R., Allen, C. E., & the NACHO-LIBRE Study Group (2019) · Blood · doi:10.1182/blood-2018-10-878363 · Cited by 123
Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia
Dodiya, H. B., Lutz, H. L., Weigle, I. Q., Patel, P., Michalkiewicz, J., Roman-Santiago, C. J., Zhang, C. M., Liang, Y., Srinath, A., Zhang, X., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20200895 · Cited by 120
Targeting microglia in brain disorders
Priller, J., & Prinz, M. (2019) · Science · doi:10.1126/science.aau9100 · Cited by 111
Self-citationHéritier, S., Barkaoui, M., Miron, J., Thomas, C., Moshous, D., Lambilliotte, A., Mazingue, F., Kébaïli, K., Jeziorski, É., Plat, G., et al. (2018) · British Journal of Haematology · doi:10.1111/bjh.15577 · Cited by 105
Mullane, K., & Williams, M. J. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113945 · Cited by 109
Resident tissue macrophages: Key coordinators of tissue homeostasis beyond immunity
Zhao, J., Andreev, I., & Silva, H. M. (2024) · Science Immunology · doi:10.1126/sciimmunol.add1967 · Cited by 106
“The BRAF V600E mutation, a common mutation affecting the RAS–MAPK kinase–extracellular signal–regulated kinase pathway, leads to a lethal neurodegenerative disease when propagated in microglia ( 168 ).”
BackgroundInfluentialHistiocytosis and the nervous system: from diagnosis to targeted therapies
Aubart, F. C., Idbaïh, A., Emile, J., Amoura, Z., Abdel-Wahab, O. I., Durham, B. H., Haroche, J., & Diamond, E. L. (2021) · Neuro-Oncology · doi:10.1093/neuonc/noab107 · Cited by 100
Self-citationA temporal perspective for tumor-associated macrophage identities and functions
Blériot, C., Dunsmore, G., Alonso‐Curbelo, D., & Ginhoux, F. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.002 · Cited by 105
mTOR-dependent translation amplifies microglia priming in aging mice
Keane, L., Antignano, I., Riechers, S., Zollinger, R., Dumas, A. A., Offermann, N., Bernis, M. E., Russ, J., Graelmann, F. J., McCormick, P. N., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci132727 · Cited by 89
“Microglia have been implicated in the pathogenesis of neuro-degenerative diseases, fueling their initiation and progression, especially through a heightened ability to respond to activation stimuli, also called priming (73, 74).”
The genesis of human hematopoietic stem cells
Calvanese, V., & Mikkola, H. K. A. (2023) · Blood · doi:10.1182/blood.2022017934 · Cited by 85
Inda, M. C., Joshi, S., Wang, T., Bolaender, A., Gandu, S. R., Koren, J., Yue, A., Taldone, T., Yan, P., Sun, W., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14082-5 · Cited by 84
Tan, H. Y., Cho, H., & Lee, L. P. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-020-00643-3 · Cited by 87
Genetic mosaicism in the human brain: from lineage tracing to neuropsychiatric disorders
Bizzotto, S., & Walsh, C. A. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00572-x · Cited by 86
Review: Somatic mutations in neurodegeneration
Leija‐Salazar, M., Piette, C. E., & Proukakis, C. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12465 · Cited by 86
Mouse models of neurodegeneration: Know your question, know your mouse
Fisher, E., & Bannerman, D. M. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaq1818 · Cited by 80
Erdheim–Chester disease: a rapidly evolving disease model
Pegoraro, F., Papo, M., Maniscalco, V., Charlotte, F., Haroche, J., & Vaglio, A. (2020) · Leukemia · doi:10.1038/s41375-020-0944-4 · Cited by 84
Modeling human yolk sac hematopoiesis with pluripotent stem cells
Atkins, M. H., Scarfò, R., McGrath, K. E., Yang, D., Palis, J., Ditadi, A., & Keller, G. M. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20211924 · Cited by 78
Papo, M., Aubart, F. C., Tréfond, L., Bauvois, A., Amoura, Z., Emile, J., & Haroche, J. (2019) · Current Oncology Reports · doi:10.1007/s11912-019-0810-6 · Cited by 77
Molecular characterization of the histiocytoses: Neoplasia of dendritic cells and macrophages
Durham, B. H. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.03.002 · Cited by 72
Self-citationPicarsic, J. L., Pysher, T. J., Zhou, H., Fluchel, M. N., Pettit, T., Whitehead, M. R., Surrey, L. F., Harding, B. N., Goldstein, G., Fellig, Y., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0811-6 · Cited by 71
Kuil, L. E., Oosterhof, N., Ferrero, G., Mikulášová, T., Hason, M., Dekker, J., Rovira, M., van der Linde, H. C., van Strien, P. M. H., de Pater, E., et al. (2020) · eLife · doi:10.7554/elife.53403 · Cited by 68
Halbritter, F., Farlik, M., Schwentner, R., Jug, G., Fortelny, N., Schnöller, T., Pisa, H., Schuster, L. C., Reinprecht, A., Czech, T., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0138 · Cited by 68
Brain Parenchymal and Extraparenchymal Macrophages in Development, Homeostasis, and Disease
Brioschi, S., Zhou, Y., & Colonna, M. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900821 · Cited by 67
Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction
Arnold, T. D., Lizama, C. O., Cautivo, K. M., Santander, N., Lin, L., Qiu, H., Huang, E. J., Liu, C., Mukouyama, Y.-S., Reichardt, L. F., et al. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20181290 · Cited by 67
Yan, J., Zuo, G., Sherchan, P., Huang, L., Ocak, U., Xu, W., Travis, Z. D., Wang, W., Zhang, J. H., & Tang, J. (2020) · Neurotherapeutics · doi:10.1007/s13311-019-00821-5 · Cited by 67
Multiple sclerosis is linked to MAPKERK overactivity in microglia
ten Bosch, G. J. A., Bolk, J., Hart, B. A. ‘., & Laman, J. D. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02080-4 · Cited by 63
“Mass et al. investigated neurodegeneration that occurs in the context of neurohistiocytosis, as this disease can harbor BRAFV600E [7].”
BackgroundInfluentialThe coming of age of Langerhans cell histiocytosis
Allen, C. E., Beverley, P. C. L., Collin, M. P., Diamond, E. L., Egeler, R. M., Ginhoux, F., Glass, C. K., Minkov, M., Rollins, B. J., & van Halteren, A. G. S. (2019) · Nature Immunology · doi:10.1038/s41590-019-0558-z · Cited by 62
Hoeijmakers, L., Lesuis, S. L., Krugers, H. J., Lucassen, P. J., & Kőrösi, A. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.02.003 · Cited by 66
Mass, E. (2018) · International Immunology · doi:10.1093/intimm/dxy044 · Cited by 65
Self-citationCecerska‐Heryć, E., Pękała, M., Serwin, N. M., Gliźniewicz, M., Grygorcewicz, B., Michalczyk, A., Heryć, R., Budkowska, M., & Dołęgowska, B. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01344-6 · Cited by 68
“However, abnormally activated glial cells (Mass et al. 2017; Goldmann et al. 2013) and B lymphocytes (Mass et al.”
BackgroundBrain Somatic Mutation in Aging and Alzheimer's Disease
Miller, M. B., Reed, H., & Walsh, C. A. (2021) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-121520-081242 · Cited by 58
“(79) developed mice expressing Braf V600E in specific yolk sac erythro-myeloid progenitors that populate the brain in early development and generate microglia, the brain tissue-resident macrophages.”
BackgroundLodato, M. A., & Walsh, C. A. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz191 · Cited by 56
“In the mouse, clonal somatic mutation of BRAF in microglial progenitors during development caused a neurodegenerative phenotype in the adult (79).”
BackgroundEpigenetic Regulation of Kupffer Cell Function in Health and Disease
Bennett, H., Troutman, T. D., Sakai, M., & Glass, C. K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.609618 · Cited by 66
“Comparative analysis of the epigenomes of tissue macrophages have also identified the nuclear receptor LXRa (encoded by Nr1h3) and SpiC as KC LDTFs (Figure 1A) (5, 24).”
BackgroundSomatic mutations in neurons during aging and neurodegeneration
Verheijen, B. M., Vermulst, M., & van Leeuwen, F. W. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1850-y · Cited by 60
“Strikingly, somatic mutations do not even need to occur in neuronal cells to cause neuropathology [82].”
BackgroundWilk, C. M., Cathomas, F., Török, O., Le Berichel, J., Park, M. D., Bigenwald, C., Heaton, G. R., Hamon, P., Troncoso, L., Scull, B. P., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.11.011 · Cited by 51
Microglial ontogeny, diversity and neurodevelopmental functions
Thion, M. S., & Garel, S. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.06.013 · Cited by 59
Fetal-Derived Immune Cells at the Roots of Lifelong Pathophysiology
Mass, E., & Gentek, R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.648313 · Cited by 47
Self-citationCentral nervous system involvement in Erdheim-Chester disease
Aubart, F. C., Idbaïh, A., Damien Galanaud, E., Law-Ye, B., Emile, J., Charlotte, F., Donadieu, J., Maksud, P., Seilhean, D., Amoura, Z., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000010748 · Cited by 45
“The limited efficacy of targeted therapies on CNS manifestations, compared to their dramatic effects in other localizations, has several potential explanations: a lower diffusion in CNS due to the blood–brain barrier; the nontumoral mechanism of pseudodegenerative lesions, in which no histiocytes are observed, leading…”
BackgroundSomatic Variants: New Kids on the Block in Human Immunogenetics
Horebeek, L. V., Dubois, B., & Goris, A. (2019) · Trends in Genetics · doi:10.1016/j.tig.2019.09.005 · Cited by 46
Xiao, Y., van Halteren, A. G. S., Lei, X., Borst, J., Steenwijk, E. C., de Wit, T., Grabowska, J. A., Voogd, R., Kemps, P. G., Picarsic, J. L., et al. (2020) · Blood · doi:10.1182/blood.2020005209 · Cited by 42
Cong, C., Kluwe, L., Li, S., Liu, X., Liu, Y., Liu, H., Gui, W., Liu, T., & Xu, L. (2019) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2019.03.030 · Cited by 38
Louadi, Z., Elkjaer, M. L., Klug, M., Lio, C. T., Fenn, A. M., Illés, Z., Bongiovanni, D., Baumbach, J., Kacprowski, T., List, M., et al. (2021) · Genome biology · doi:10.1186/s13059-021-02538-1 · Cited by 36
Modeling Alzheimer’s disease with human iPS cells: advancements, lessons, and applications
Essayan-Perez, S., Zhou, B., Nabet, A. M., Wernig, M., & Huang, Y. A. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104503 · Cited by 40
Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction
Bourseguin, J., Cheng, W., Talbot, E., Hardy, L., Lai, J. F., Jeffries, A. M., Lodato, M. A., Lee, E. A., & Khoronenkova, S. V. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac104 · Cited by 36
“For example, somatic mutations in the BRAF oncogene in erythro-myeloid precursors of microglia result in progressive neurological impairment with multiple features of cerebellar ataxia (7).”
Yan, M., Sun, Z., Zhang, S., Yang, G., Jiang, X. Y., Wang, G., Li, R., Wang, Q., & Tian, X. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.110988 · Cited by 38
“…markers of inflammation and changes in immune cells in the autopsy pathology specimens of patients with various neurosystemic diseases, such as Parkinson ’ s Disease (PD), multiple sclerosis (MS), and stroke (Mass et al., 2017; Wang et al., 2023; Lambertsen et al., 2019; Tansey et al., 2022).”
BackgroundSpecialized functions of resident macrophages in brain and heart
Nicolás-Ávila, J. Á., Hidalgo, A., & Ballesteros, I. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.6mr0118-041r · Cited by 35
Mosaic loss of Chromosome Y in aged human microgliaPreprint
Vermeulen, M., Pearse, R. V., Young‐Pearse, T. L., & Mostafavi, S. (2022) · Genome Research · doi:10.1101/gr.276409.121 · Cited by 35
Synapse Dysfunctions in Multiple Sclerosis
Schwarz, K., & Schmitz, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021639 · Cited by 35
“However, also abnormally activated glial cells [23,24] and B-lymphocytes play an important role [22,25–31].”
BackgroundMAP-Kinase-Driven Hematopoietic Neoplasms: A Decade of Progress in the Molecular AgePreprint
Chakraborty, R., Abdel-Wahab, O. I., & Durham, B. H. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a034892 · Cited by 31
Self-citationSomatic mutations in autoinflammatory and autoimmune disease
Torreggiani, S., Castellan, F. S., Aksentijevich, I. A., & Beck, D. B. (2024) · Nature Reviews Rheumatology · doi:10.1038/s41584-024-01168-8 · Cited by 29
Koizumi, T., Taguchi, K., Mizuta, I., Toba, H., Ohigashi, M., Onishi, O., Ikoma, K., Miyata, S., Nakata, T., Tanaka, M., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1467-7 · Cited by 29
Prenatal Origin of Pediatric Leukemia: Lessons From Hematopoietic Development
Cazzola, A., Cazzaniga, G., Biondi, A., Meneveri, R., Brunelli, S., & Azzoni, E. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.618164 · Cited by 29
The Microglial Response to Neurodegenerative Disease
Song, W. M., & Colonna, M. (2018) · Advances in immunology · doi:10.1016/bs.ai.2018.04.002 · Cited by 30
Yue, W., Deng, X., Wang, Z., Jiang, M., Hu, R., Duan, Y., Wang, Q., Cui, J., & Fang, Y. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00354-8 · Cited by 26
“For example, ERKactivated microglia were shown to drive astrogliosis, synaptic loss, neuronal death and neurobehavioral deficits in mice [32], while activation of the NF-κB signaling in microglia induced motor neuron loss in ALS [33].”
BackgroundAn update on the treatment of pediatric-onset Langerhans cell histiocytosis through pharmacotherapy
Minkov, M. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1429405 · Cited by 25
“Geissmann sheds light on the underlying mechanism of the neurodegenerative CNS-LCH with possible therapeutic implications [48].”
BackgroundFrom macrophage biology to macrophage-based cellular immunotherapies
Mass, E., & Lachmann, N. (2021) · Gene Therapy · doi:10.1038/s41434-021-00221-5 · Cited by 24
Self-citationOne Size Does Not Fit All: Heterogeneity in Developmental Hematopoiesis
Barone, C., Orsenigo, R., Meneveri, R., Brunelli, S., & Azzoni, E. (2022) · Cells · doi:10.3390/cells11061061 · Cited by 25
A microglia clonal inflammatory disorder in Alzheimer’s disease
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B., Socci, N. D., Alberdi, A., Baako, A., et al. (2025) · eLife · doi:10.7554/elife.96519.3 · Cited by 21
“…associated with neurodegeneration ( Mass et al., 2017 ; Boyd et al., 2020 ; Bhatia et al., 2020 ; Diamond et al., 2016 ), and introduction in mouse microglia of the variant allele most frequently associated with histiocytosis (BRAF V600E ) causes neurodegeneration in mice ( Mass et al., 2017 ).”
InfluentialSelf-citationIDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation
Park, J. W., Kwak, J., Kim, K. W., Jung, S., Nam, C. H., Kim, H. J., Lee, S. M., Choi, C., Ahn, Y., Park, J., et al. (2026) · Science · doi:10.1126/science.adt0559 · Cited by 23
Tumorigenic Interplay Between Macrophages and Collagenous Matrix in the Tumor Microenvironment
Varol, C. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9095-5_15 · Cited by 21
Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy
Kim, J., Park, S. M., Koh, H. Y., Ko, A., Kang, H., Chang, W. S., Kim, D. S., & Lee, J. H. (2024) · Brain · doi:10.1093/brain/awae190 · Cited by 20
Vaiani, E., Felizzia, G., Lubieniecki, F. J., Braier, J. L., & Belgorosky, A. (2021) · Hormone Research in Paediatrics · doi:10.1159/000517040 · Cited by 20
Allogenic microglia replacement: A novel therapeutic strategy for neurological disorders
Rao, Y., & Peng, B. (2023) · Fundamental Research · doi:10.1016/j.fmre.2023.02.025 · Cited by 18
“Mass and colleagues demonstrated that the mosaic BRAF V600E mutation in microglia causes the clonal expansion of dysfunctional microglia, leading to the formation of astrogliosis, the deposition of A 𝛽 , loss of synapse, and a decline in cognitive function [117] .”
BackgroundPizzirusso, G., Preka, E., Goikolea, J., Aguilar-Ruiz, C., Rodriguez‐Rodriguez, P., Vázquez-Cabrera, G., Laterza, S., Latorre‐Leal, M., Eroli, F., Blomgren, K., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.04.009 · Cited by 21
“Our findings suggest that microglia dynamic alterations might represent a turning point in AD pathology progression, contributing to Aβ plaque formation, FSI dysfunction, and circuit failure in the hippocampus.”
Horebeek, L. V., Hilven, K., Mallants, K., van Nieuwenhuijze, A. E. M., Kelkka, T., Savola, P., Mustjoki, S. M., Schlenner, S., Liston, A., Dubois, B., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy425 · Cited by 17
“For some somatic variants, it may even be possible to target the affected pathway itself, as examples such as BRAF or STAT3 inhibitors for other autoimmune and neurological diseases illustrate (18,19).”
Advances in Genetic and Molecular Understanding of Alzheimer’s Disease
Ibáñez, L., Cruchaga, C., & Fernández, M. V. (2021) · Genes · doi:10.3390/genes12081247 · Cited by 20
“While no mutations have been found within the MAPK pathway that are associated with AD, somatic mutations in the BRAF gene (which is part of the MAPK pathway) in the erythro-myeloid progenitor lineage in mice may cause neurodegeneration [26].”
BackgroundRole of Microglia in Central Nervous System Development and PlasticityPreprint
Schafer, D. P., Stevens, B., Bennett, M. L., & Bennett, F. C. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041810 · Cited by 19
Metadata
- Authors
- Mass, E., Jacome-Galarza, C. E., Blank, T., Lazarov, T., Durham, B. H., Ozkaya, N., Pastore, A., Schwabenland, M., Chung, Y. R., Rosenblum, M. K., Prinz, M., Abdel-Wahab, O., & Geissmann, F.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Freiburg (DE)
- ORCID
- Venue
- Nature
- Published
- 2017-08-30
- Volume
- 549
- Issue
- 7672
- Pages
- 389-393
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6047345
- OpenAlex
- W2750719748
- Cited by
- 210
- References
- 41
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 29 · 2023: 18 · 2022: 12 · 2021: 27 · 2020: 27 · 2019: 29 · 2018: 26 · 2017: 7
- FWCI
- 12.07
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL138090)
- National Cancer Institute (R01CA201247, P30CA008748)
- National Institute of Allergy and Infectious Diseases (R01AI130345)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- neurodegeneration, microglia, erythro-myeloid progenitors, BRAF V600E mutation, Ras/MEK/ERK pathway, histiocytosis, clonal expansion, MAPK signaling, astrocyte activation, amyloid precursor protein, synaptic loss, neuronal cell death, BRAF inhibition, yolk sac, tissue-resident macrophages, glial activation
- MeSH terms
- Animals, Clone Cells, Disease Models, Animal, Female, Humans, Macrophages, Male, Mosaicism, Mutation, Histiocytosis, Erythroid Precursor Cells, Microglia, Neurodegenerative Diseases, MAP Kinase Signaling System, Myeloid Progenitor Cells, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
