Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice

Noriyuki Kishi, Jessica L. MacDonald, Julia Ye, Bradley J. Molyneaux, Eiman Azim and Jeffrey D. Macklis ()
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Noriyuki Kishi: Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
Jessica L. MacDonald: Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
Julia Ye: Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
Bradley J. Molyneaux: Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
Eiman Azim: Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
Jeffrey D. Macklis: Center for Brain Science, and Harvard Stem Cell Institute, Harvard University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10520

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