Wild-type microglia arrest pathology in a mouse model of Rett syndrome
Open accessAbstract
Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
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Inflammation is a key manifestation of Mecp2 mutation in non-neural cells.
“Inflammation is a key manifestation of Mecp2 mutation in non-neural cells14.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [14]
In the indexed passage labeled Abstract (page not supplied), the paper reports that Mecp2-null microglia have impaired responses to immunological stimuli and reduced phagocytic capacity. This supports altered immune-cell function, but the paper does not identify inflammation as a key manifestation of Mecp2 mutation in non-neural cells. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTransplantation of wild-type bone marrow to introduce microglial cells into the Mecp2 knockout mouse model of Rett syndrome resulted in increased lifespan, normalization of breathing patterns, reduction of apnea, normalization of body weight and improved locomotor activity.
“Recently, Derecki et al. 47 used transplantation of wild-type bone marrow to introduce microglial cells into the Mecp2 knockout mouse model of Rett syndrome. This resulted in increased lifespan, normalization of breathing patterns, reduction of apnea, normalization of body weight and improved locomotor activity in these mice 47 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [47]
Based on animal work, trials that aim to rebuild immune cells in people with ASD have begun.
“clinical trials using strategies to reconstitute immune cells in individuals with ASD have been initiated233,234.”
From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [233]
Microglia have been identified as cells capable of restoring neural function in the ASD-model MECP2 knockout mice.
“Recently, microglia have been identified as cells capable of restoring neural function in the ASD-model MECP2 knockout mice37.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [37]
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- Authors
- Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., & Kipnis, J.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Kipnis, Jonathan
- Venue
- Nature
- Published
- 2012-03-18
- Volume
- 484
- Issue
- 7392
- Pages
- 105-109
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3321067
- OpenAlex
- W2020407498
- Cited by
- 607
- References
- 30
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 25 · 2023: 23 · 2022: 24 · 2021: 36 · 2020: 31 · 2019: 38 · 2018: 43 · 2017: 44 · 2016: 55 · 2015: 65 · 2014: 73 · 2013: 77 · 2012: 47
- FWCI
- 50.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Hartwell Foundation
- National Institute on Aging (AG034113, R01AG034113, R37AG034113)
- National Institute of Neurological Disorders and Stroke (R01NS081026)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD056293, HD056293)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Rett syndrome, MeCP2, microglia, bone marrow transplantation, lifespan extension, breathing abnormalities, locomotor activity, insulin-like growth factor I, myeloid cells, cranial irradiation, mouse model
- MeSH terms
- Animals, Body Weight, Brain, Disease Models, Animal, Female, Insulin-Like Growth Factor I, Locomotion, Male, Mice, Inbred C57BL, Phagocytosis, Phosphatidylserines, Respiration, Rett Syndrome, Bone Marrow Transplantation, Apoptosis, Annexin A5, Microglia, Disease Progression, Rotarod Performance Test, Mice, Methyl-CpG-Binding Protein 2
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