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


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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Figure 1: MeCP2 is present in all glial cell types in normal rat and mouse brains.
Figure 2: MeCP2 is detected in astrocytes in brain sections from MeCP2+/y, but not MeCP2−/y, mice.
Figure 3: Wild-type hippocampal neurons cocultured with cortical astrocytes from RTT mice have stunted dendrites.
Figure 4: Conditioned medium from Mecp2−/y astrocytes cannot support normal neuronal growth.
Figure 5: Altered morphology of wild-type neurons cultured with ACM from Mecp2−/y astrocytes is evident at the single cell level.


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The authors thank J. Levine and L. Evans for providing the enriched glial cultures for the initial immunostaining analysis; P. Brehm, R. Goodman, T. Reese and G. Banker for valuable discussions about the results; and D.D. Lu and R. Spektor for technical assistance. This work was supported in part by a grant from the International Rett Syndrome Foundation to N.B. and a US National Institutes of Health grant to G.M. and N.B. G.M. is an Investigator of the Howard Hughes Medical Institute.

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N.B., D.T.L., C.G. and G.M. designed the experiments. N.B., D.T.L. and C.G. carried out the experiments. N.B., D.T.L. and G.M. wrote the paper. N.B. and G.M. supervised the project.

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Correspondence to Nurit Ballas.

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Ballas, N., Lioy, D., Grunseich, C. et al. Non–cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 12, 311–317 (2009).

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