Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice
Molyneaux, Bradley J.
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CitationKishi, Noriyuki, Jessica L. MacDonald, Julia Ye, Bradley J. Molyneaux, Eiman Azim, and Jeffrey D. Macklis. 2016. “Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice.” Nature Communications 7 (1): 10520. doi:10.1038/ncomms10520. http://dx.doi.org/10.1038/ncomms10520.
AbstractMutations 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:26318703