title: Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice.
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.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kishi
authors.affiliation: Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: MacDonald
authors.affiliation: Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Molyneaux
authors.affiliation: Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Eiman
authors.initials: E
authors.lastname: Azim
authors.affiliation: Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Macklis
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D016328:NF-kappa B; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse
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