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

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  • Noriyuki Kishi

    (Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
    Present address: Laboratory for Marmoset Neural Architecture, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan)

  • Jessica L. MacDonald

    (Center for Brain Science, and Harvard Stem Cell Institute, Harvard University
    Present address: Department of Biology, Syracuse University, Syracuse, New York 13244, USA)

  • 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
    Present address: Departments of Neurology and Critical Care, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA)

  • 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)

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.

Suggested Citation

  • Noriyuki Kishi & Jessica L. MacDonald & Julia Ye & Bradley J. Molyneaux & Eiman Azim & Jeffrey D. Macklis, 2016. "Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10520
    DOI: 10.1038/ncomms10520
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