Mice deficient in NRROS show abnormal microglial development and neurological disorders
Abstract
Microglia and other tissue-resident macrophages within the central nervous system (CNS) have essential roles in neural development, inflammation and homeostasis. However, the molecular pathways underlying their development and function remain poorly understood. Here we report that mice deficient in NRROS, a myeloid-expressed transmembrane protein in the endoplasmic reticulum, develop spontaneous neurological disorders. NRROS-deficient (Nrros-/-) mice show defects in motor functions and die before 6 months of age. Nrros-/- mice display astrogliosis and lack normal CD11b hi CD45 lo microglia, but they show no detectable demyelination or neuronal loss. Instead, perivascular macrophage-like myeloid cells populate the Nrros-/- CNS. Cx3cr1-driven deletion of Nrros shows its crucial role in microglial establishment during early embryonic stages. NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function. Our study reveals a NRROS-mediated pathway that controls CNS-resident macrophage development and affects neurological function.
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Gene expression profiles of cortical microglia from Emx1Cre:Itgb8fl/fl mice were correlated with Tgfbr2-cKO microglia and previously published microglia transcriptomes from Nrros-KO and Smad2/Smad3-cKO mice.
“Gene expression profiles of cortical microglia from Emx1 Cre : Itgb8 fl/fl mice were correlated with Tgfbr2 -cKO microglia (Fig. 8j) and previously published microglia transcriptomes from Nrros -KO 40 and Smad2 / Smad3 -cKO mice (Extended Data Fig. 9e-h).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [40]
Blocking TGF-beta signaling has no major effect on microglial cell number but causes a drastic gene-expression shift, including widespread upregulation of genes found in Cluster 6 and brain border macrophages, including Mrc1.
“blocking TGF-beta signaling (which helps to confer microglia identity, (Butovsky et al., 2014)) has no major effect on microglia cell number, but causes a drastic shift in their gene expression including widespread upregulation of (or failure to downregulate) genes found in Cluster 6 microglia and in brain border macrophages, including Mrc1 (Wong et al., 2017).”
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 Wong et al., 2017
NRROS-deficient mice lack microglia and are populated by perivascular macrophage-like cells, showing NRROS is important for the programme generating the homeostatic microglial phenotype.
“Mice deficient in negative regulator of reactive oxygen species (NRROS), which is preferentially expressed in myeloid cells (including macrophages, neutrophils, microglia and perivascular macrophages) and regulates the production of reactive oxygen species, lack microglia and instead are populated by perivascular macrophage-like cells87.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [87]
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- Authors
- Wong, K., Noubade, R., Manzanillo, P., Ota, N., Foreman, O., Hackney, J. A., Friedman, B. A., Pappu, R., Scearce-Levie, K., & Ouyang, W.
- Affiliations
- Genentech (US)
- Corresponding author
- Wong, Kit
- Ouyang, Wenjun
- ORCID
- Venue
- Nature Immunology
- Published
- 2017-05-01
- Volume
- 18
- Issue
- 6
- Pages
- 633-641
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2610661410
- Cited by
- 71
- References
- 61
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 13 · 2017: 3
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- microglial development, endoplasmic reticulum, tissue-resident macrophages, neurological disorders, astrocyte activation, CX3CR1, SALL1, motor impairment
- MeSH terms
- Animals, Astrocytes, Central Nervous System, Flow Cytometry, Immunohistochemistry, Lameness, Animal, Locomotion, Macrophages, Membrane Proteins, Nervous System Diseases, Posture, Proteins, Transcription Factors, Urinary Incontinence, Blotting, Western, Urinary Retention, Microglia, Mice, Knockout, Gene Expression Regulation, Developmental, Myeloid Cells, Mice, Latent TGF-beta Binding Proteins
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