TY - JOUR
T1 - Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice
AU - Kishi, Noriyuki
AU - MacDonald, Jessica L.
AU - Ye, Julia
AU - Molyneaux, Bradley J.
AU - Azim, Eiman
AU - Macklis, Jeffrey D.
N1 - Publisher Copyright:
© 2016, NPG. All rights reserved.
PY - 2016/1/29
Y1 - 2016/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961289783&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961289783&partnerID=8YFLogxK
U2 - 10.1038/ncomms10520
DO - 10.1038/ncomms10520
M3 - Article
C2 - 26821816
AN - SCOPUS:84961289783
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 10520
ER -