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In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of <jats:italic>Irak1<\/jats:italic>, a central component of the NF-\u03baB pathway. We show that overexpression of <jats:italic>Irak1<\/jats:italic> mimics the reduced dendritic complexity of <jats:italic>Mecp2<\/jats:italic>-null cortical callosal projection neurons (CPN), and that NF-\u03baB signalling is upregulated in the cortex with <jats:italic>Mecp2<\/jats:italic> loss-of-function. Strikingly, we find that genetically reducing NF-\u03baB signalling in <jats:italic>Mecp2<\/jats:italic>-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-\u03baB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-\u03baB pathway modulation.<\/jats:p>","DOI":"10.1038\/ncomms10520","type":"journal-article","created":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T10:24:27Z","timestamp":1454063067000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Reduction of aberrant NF-\u03baB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice"],"prefix":"10.1038","volume":"7","author":[{"given":"Noriyuki","family":"Kishi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley J.","family":"Molyneaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiman","family":"Azim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Macklis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,29]]},"reference":[{"key":"BFncomms10520_CR1","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.neuron.2007.10.001","volume":"56","author":"M Chahrour","year":"2007","unstructured":"Chahrour, M. & Zoghbi, H. 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