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Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740176/ https://www.ncbi.nlm.nih.gov/pubmed/26821816 http://dx.doi.org/10.1038/ncomms10520 |
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author | Kishi, Noriyuki MacDonald, Jessica L. Ye, Julia Molyneaux, Bradley J. Azim, Eiman Macklis, Jeffrey D. |
author_facet | Kishi, Noriyuki MacDonald, Jessica L. Ye, Julia Molyneaux, Bradley J. Azim, Eiman Macklis, Jeffrey D. |
author_sort | Kishi, Noriyuki |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4740176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47401762016-03-04 Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice Kishi, Noriyuki MacDonald, Jessica L. Ye, Julia Molyneaux, Bradley J. Azim, Eiman Macklis, Jeffrey D. Nat Commun Article 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. Nature Publishing Group 2016-01-29 /pmc/articles/PMC4740176/ /pubmed/26821816 http://dx.doi.org/10.1038/ncomms10520 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Kishi, Noriyuki MacDonald, Jessica L. Ye, Julia Molyneaux, Bradley J. Azim, Eiman Macklis, Jeffrey D. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice |
title | Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice |
title_full | Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice |
title_fullStr | Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice |
title_full_unstemmed | Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice |
title_short | Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice |
title_sort | reduction of aberrant nf-κb signalling ameliorates rett syndrome phenotypes in mecp2-null mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740176/ https://www.ncbi.nlm.nih.gov/pubmed/26821816 http://dx.doi.org/10.1038/ncomms10520 |
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