Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology.

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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Available from: Christopher Grunseich, Jul 31, 2014
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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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    • "However, more recent studies have shown that MeCP2 is also expressed in all glial cell types, including astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia (Ballas et al., 2009; Derecki et al., 2012). In particular, in vitro studies have shown that astrocytic MeCP2 supports normal neuronal morphology, indicating a non-cell autonomous influence of MeCP2 on neuronal function (Ballas et al., 2009; Maezawa et al., 2009). Global re-expression of the MeCP2 gene postnatally in full MeCP2 KO mice demonstrated disease reversibility in this RTT mouse model, suggesting that the neurological defects in MeCP2 disorders are not permanent (Guy et al., 2007). "
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    ABSTRACT: Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized as important mediators of normal brain function as well as neurodevelopmental, neurological, and neurodegenerative brain diseases. Although numerous potential mechanisms have been proposed to explain the role of astrocytes in the normal and diseased brain, research into the physiological relevance of these mechanisms in vivo is just beginning. In this review, we will summarize recent developments in innovative and powerful molecular approaches, including knockout mouse models, transgenic mouse models, and astrocyte-targeted gene transfer/expression, which have led to advances in understanding astrocyte biology in vivo that were heretofore inaccessible to experimentation. We will examine the recently improved understanding of the roles of astrocytes - with an emphasis on astrocyte signaling - in the context of both the healthy and diseased brain, discuss areas where the role of astrocytes remains debated, and suggest new research directions.
    Frontiers in Cellular Neuroscience 12/2013; 7:272. DOI:10.3389/fncel.2013.00272 · 4.18 Impact Factor
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    • "Third, mutation of MECP2, an X-linked gene encoding the epigenetic factor methyl-CpG-binding protein-2 is associated with Rett syndrome (RS). Although it was thought that the primary cause resulted from a lack of functional MECP2 in neurones, it was later demonstrated that the loss of MECP2 occurs also in astroglia (Ballas et al., 2009). In addition, it was found that MECP2-null microglial cells exert a potent glutamate-mediated neurotoxic activity to hippocampal neurones. "
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