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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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    • "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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    • "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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    • "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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