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 - Funding Information:
We thank Drs Adrian Bird and Rudolf Jaenisch for generously sharing their labs’ Mecp2 mutant mice, Dr Athena Andreadis for the mouse tau promoter plasmid and Dr Zhaolan Zhou for the shMecp2 plasmid. We thank Dr Paola Arlotta for her critical early advice on the gene expression analyses in this study. We thank Kathryn Quinn, Ashley Palmer, Ted Yamamoto, Lincoln Pasquina, Brian Brandler, Erica Gornstein and Ryan Richardson for technical assistance. This work was partially supported by grants from the RSRF and IRSF to JDM, by infrastructure supported by NINDS grants NS41590, NS45523, NS49553 and NS075672 to JDM, and by the Jane and Lee Seidman Fund for CNS Research, and the Emily and Robert Pearlstein Fund for Nervous System Repair. N.K. was partially supported by fellowships from the Rett Syndrome Research Foundation (RSRF)/International Rett Syndrome Foundation (IRSF), the Japan Society for the Promotion of Science (JSPS), and the Uehara Memorial Foundation. E.A. was partially supported by a US National Institutes of Health individual predoctoral National Research Service Award fellowship (F31 NS060421).
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.
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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 -