Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice
Open accessAbstract
Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation.
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MeCP2 directly represses Irak1.
“Notably, MeCP2 directly represses Irak1 and downregulation of the NF-κβ pathway improves symptoms in Mecp2 null mice [206].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [206]
In Results, under “CNS-specific mis-regulation of Irak1 in Mecp2-null mice” (page unavailable), MeCP2 binds upstream of Irak1, and reducing MeCP2 increases Irak1 expression. The authors say direct regulation is possible, but do not establish the unqualified claim that MeCP2 directly represses Irak1. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDownregulation of the NF-κβ pathway improves symptoms in Mecp2 null mice.
“Notably, MeCP2 directly represses Irak1 and downregulation of the NF-κβ pathway improves symptoms in Mecp2 null mice [206].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [206]
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- Authors
- Kishi, N., MacDonald, J. L., Ye, J., Molyneaux, B. J., Azim, E., & Macklis, J. D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Macklis, Jeffrey D.
- Venue
- Nature Communications
- Published
- 2016-01-29
- Volume
- 7
- Issue
- 1
- Pages
- 10520-10520
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4740176
- OpenAlex
- W2365381881
- Cited by
- 69
- References
- 71
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 8 · 2018: 8 · 2017: 6 · 2016: 2
- FWCI
- 6.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- International Rett Syndrome Foundation
- Uehara Memorial Foundation
- National Institutes of Health (NS45523, NS41590)
- Japan Society for the Promotion of Science
- National Institute of Neurological Disorders and Stroke (R01NS045523, NS075672, NS 49553, NS 41590, R37NS041590, R01NS049553, R01NS041590, R01NS075672, NS45523, F31NS060421)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Rett syndrome, MeCP2, NF-κB signaling, IRAK1, dendritic complexity, callosal projection neurons, cerebral cortex, lifespan extension, neurodevelopmental disorders, therapeutic target
- MeSH terms
- Animals, Female, Gene Expression Regulation, Male, Signal Transduction, Rett Syndrome, NF-kappa B, Mice, Knockout, Mice, Methyl-CpG-Binding Protein 2, Interleukin-1 Receptor-Associated Kinases
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