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Ballas N, Lioy DT, Grunseich C, Mandel G. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 12: 311-317

Howard Hughes Medical Institute, Department of Neurobiology and Behavior, State University of New York, Stony Brook, New York 11794, USA. (
Nature Neuroscience (Impact Factor: 14.98). 04/2009; 12(3):311-7. DOI: 10.1038/nn.2275
Source: PubMed

ABSTRACT The neurodevelopmental disorder Rett syndrome (RTT) is caused by sporadic mutations in the transcriptional factor methyl-CpG-binding protein 2 (MeCP2). Although it is thought that the primary cause of RTT is cell autonomous, resulting from a lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease is unknown. We found that the loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brains. Using an in vitro co-culture system, we found that mutant astrocytes from a RTT mouse model, and their conditioned medium, failed to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that astrocytes in the RTT brain carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, probably as a result of aberrant secretion of soluble factor(s).

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    • "In vitro experiments by Ballas et al . ( 2009 ) found that hippocampal neurons cultured with MeCP2 deleted astrocytes or their conditioned medium , failed to show normal dendritic development . Impaired dendrite formation by astrocytic MeCP2 occurs independent of the presence of neural MeCP2 , suggesting that dysregulation of astrocytic soluble factors induced by MeCP2 deletion may"
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    • "Neuronal morphology is also influenced by nearby glial cells (Giordano et al., 2011). The absence of MeCP2 in adjacent glial cells has also been shown to be influencing the neuronal morphology (Ballas et al., 2009). In differentiating neural stem cells, both neurons and glia are present simultaneously, thus any altered MeCP2 expression in glial cells could potentially influence the neuronal morphology. "
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    ABSTRACT: Methyl CpG Binding Protein 2 (MeCP2) is an important epigenetic factor in brain. MeCP2 expression is affected by different environmental insults including alcohol exposure. Accumulating evidence supports the role of aberrant MeCP2 expression in ethanol exposure-induced neurological symptoms. However, the underlying molecular mechanisms of ethanol-induced MeCP2 deregulation remain elusive. To study the effect of ethanol on Mecp2/MeCP2 expression during neurodifferentiation, we established an in vitro model of ethanol exposure, using differentiating embryonic brain-derived neural stem cells (NSC). Previously, we demonstrated the impact of DNA methylation at the Mecp2 regulatory elements (REs) on Mecp2/MeCP2 expression in vitro and in vivo. Here, we studied whether altered DNA methylation at these REs is associated with the Mecp2/MeCP2 misexpression induced by ethanol. Binge-like and continuous ethanol exposure upregulated Mecp2/MeCP2, while ethanol withdrawal downregulated its expression. DNA methylation analysis by methylated DNA immunoprecipitation indicated that increased 5-hydroxymethylcytosine (5hmC) and decreased 5-methylcytosine (5mC) enrichment at specific REs were associated with upregulated Mecp2/MeCP2 following continuous ethanol exposure. The reduced Mecp2/MeCP2 expression upon ethanol withdrawal was associated with reduced 5hmC and increased 5mC enrichment at these REs. Moreover, ethanol altered global DNA methylation (5mC and 5hmC). Under the tested conditions, ethanol had minimal effects on NSC cell fate commitment, but caused changes in neuronal morphology and glial cell size. Taken together, our data represent an epigenetic mechanism for ethanol-mediated misexpression of Mecp2/MeCP2 in differentiating embryonic brain cells. We also show the potential role of DNA methylation and MeCP2 in alcohol-related neurological disorders, specifically Fetal Alcohol Spectrum Disorders.
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    • "Neurons are primarily affected in the disease with dendritic and synaptic abnormalities [9, 112] and studies have initially supported an exclusively neuronal role for Mecp2 in RTT pathology. However, neuron-restricted expression of Mecp2 protein is insufficient to fully rescue the disease phenotype and glial cells were also shown to play a major role in the physiopathology of the disease [6, 12, 95]. Expression of Mecp2 in astrocytes was shown to arrest disease progression in Mecp2-null mice [91] and the toxicity of Mecp2-null microglia to neurons was suggested. "
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