Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice

Nature Communications
Noriyuki KishiJeffrey D Macklis

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.

References

Aug 1, 1995·Archives of Neurology·B EgaasO Saitoh
Mar 1, 1995·Journal of Neuropathology and Experimental Neurology·D ArmstrongR Trivedi
Apr 8, 2004·Proceedings of the National Academy of Sciences of the United States of America·Sandra LuikenhuisRudolf Jaenisch
Sep 8, 2004·Human Molecular Genetics·Ann L CollinsHuda Y Zoghbi
Jan 1, 2005·Trends in Neurosciences·Mollie K Meffert, David Baltimore
Jan 4, 2005·Biochimica Et Biophysica Acta·Lei GaoAthena Andreadis
Dec 19, 2006·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Daniela del GaudioBenjamin B Roa
Feb 3, 2007·Proceedings of the National Academy of Sciences of the United States of America·Emanuela GiacomettiRudolf Jaenisch
Jul 20, 2007·Human Molecular Genetics·Matías Alvarez-SaavedraJuan I Young
Oct 5, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Stephen E P SmithPaul H Patterson
Nov 9, 2007·Neuron·Maria Chahrour, Huda Y Zoghbi
Apr 2, 2008·Neurobiology of Disease·Krassimira GarbettAntonio M Persico
Aug 15, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Humberto GutierrezAlun M Davies
Nov 8, 2008·PloS One·Rocio G UrdinguioManel Esteller
Feb 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Daniela TropeaMriganka Sur
Apr 3, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Megumi AdachiLisa M Monteggia
Sep 15, 2009·Biological Psychiatry·Thomas W Frazier, Antonio Y Hardan
Sep 19, 2009·Development·Núria GavaldàAlun M Davies
Oct 2, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Bradley J MolyneauxJeffrey D Macklis
Oct 9, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Lydia WoodGordon M G Shepherd
Dec 17, 2009·American Journal of Human Genetics·Ganeshwaran H MochidaChristopher A Walsh
Dec 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Rodney C SamacoJeffrey L Neul
Apr 29, 2010·Current Psychiatry Reports·Michael L Gonzales, Janine M LaSalle
Aug 19, 2010·Epigenetics : Official Journal of the DNA Methylation Society·Rocio G UrdinguioManel Esteller
Apr 5, 2011·Trends in Neurosciences·Humberto Gutierrez, Alun M Davies
Apr 8, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Matthew C H BoersmaMollie K Meffert
Jul 1, 2011·Nature·Daniel T LioyGail Mandel
Jul 15, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Christopher S WardJeffrey L Neul
Aug 13, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sara Anna BoniniMaurizio Memo
Feb 4, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Danielle A SchmidDavid M Katz
Mar 20, 2012·Nature·Noël C DereckiJonathan Kipnis

❮ Previous
Next ❯

Citations

Jan 18, 2013·PloS One·Vibhakar C KotakDan H Sanes
Apr 26, 2011·Trends in Molecular Medicine·Kartik Ramamoorthi, Yingxi Lin
Jan 10, 2017·Clinics and Research in Hepatology and Gastroenterology·Jing ZhaoKai Wang
Mar 1, 2017·Journal of Pharmaceutical and Biomedical Analysis·Elena FarcaşMarianne Fillet
Oct 11, 2017·Disease Models & Mechanisms·M van der VaartD Traver
Feb 16, 2018·Open Biology·Stephanie M KyleMonica J Justice
Aug 15, 2019·International Journal of Molecular Sciences·Silvia VidalJudith Armstrong
Jan 6, 2018·Molecular Psychiatry·Hao HuHossein Najmabadi
Jul 13, 2018·Orphanet Journal of Rare Diseases·Stephen Shovlin, Daniela Tropea
Dec 21, 2017·Journal of Neuroinflammation·Elizabeth NanceSujatha Kannan
Feb 9, 2021·Frontiers in Genetics·Katrina V GoodJuan Ausió

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE50225
BC004778

Methods Mentioned

BETA
fluorescence-activated cell sorting
PCR
FACS
immunoprecipitation
in vitro transcription
Protein Assay
Assay

Software Mentioned

Rosetta Resolver
GraphPad
Rosetta
ImageJ
Zen
GraphPad Prism
Elements
Photoshop

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.