Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

Mutations in the gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regula...

Full description

Saved in:
Bibliographic Details
Published in:eLife 2016-10, Vol.5
Main Authors: Sampathkumar, Charanya, Wu, Yuan-Ju, Vadhvani, Mayur, Trimbuch, Thorsten, Eickholt, Britta, Rosenmund, Christian
Format: Article
Language:English
Subjects:
Acids
Animals
Autocrine signalling
Axonogenesis
BDNF
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - metabolism
cell autonomous
Cell Differentiation
Cell Proliferation
Cellular signal transduction
Disease Models, Animal
Gene mutation
Genetic aspects
glutamatergic
Glutamatergic transmission
Health aspects
Male
MeCP2 protein
Methyl-CpG binding protein
Methyl-CpG-Binding Protein 2 - genetics
Methyl-CpG-Binding Protein 2 - metabolism
Mice, Inbred C57BL
Mice, Knockout
Molecular modelling
Morphology
Mutation
Nervous system
Neural circuitry
Neurodevelopmental disorders
Neurons
Neurons - physiology
Neuroscience
Rett syndrome
Rett Syndrome - physiopathology
Rodents
Signal Transduction
Synapses
synaptic transmission
Synaptogenesis
Transcription
TrkB receptors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Mutations in the gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons and . These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.19374