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. 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. Rett syndrome is a neurodevelopmental disorder caused by mutations in Mecp2 . Here the authors show that Mecp2 loss-of-function leads to upregulation of the NF-κB pathway, and that reducing NF-κB signalling ameliorates phenotypes of Mecp2 -null mice, thus offering a potential therapeutic strategy.