Disease Modeling Using Embryonic Stem Cells: MeCP2 Regulates Nuclear Size and RNA Synthesis in Neurons

Biozentrum, University of Basel, Basel, Switzerland.
Stem Cells (Impact Factor: 6.52). 10/2012; 30(10):2128-39. DOI: 10.1002/stem.1180
Source: PubMed


Mutations in the gene encoding the methyl-CpG-binding protein MECP2 are the major cause of Rett syndrome, an autism spectrum disorder mainly affecting young females. MeCP2 is an abundant chromatin-associated protein, but how and when its absence begins to alter brain function is still far from clear. Using a stem cell-based system allowing the synchronous differentiation of neuronal progenitors, we found that in the absence of MeCP2, the size of neuronal nuclei fails to increase at normal rates during differentiation. This is accompanied by a marked decrease in the rate of ribonucleotide incorporation, indicating an early role of MeCP2 in regulating total gene transcription, not restricted to selected mRNAs. We also found that the levels of brain-derived neurotrophic factor (BDNF) were decreased in mutant neurons, while those of the presynaptic protein synaptophysin increased at similar rates in wild-type and mutant neurons. By contrast, nuclear size, transcription rates, and BDNF levels remained unchanged in astrocytes lacking MeCP2. Re-expressing MeCP2 in mutant neurons rescued the nuclear size phenotype as well as BDNF levels. These results reveal a new role of MeCP2 in regulating overall RNA synthesis in neurons during the course of their maturation, in line with recent findings indicating a reduced nucleolar size in neurons of the developing brain of mice lacking Mecp2. STEM Cells2012;30:2128-2139.

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Available from: Ruben Deogracias, Apr 14, 2014
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    • "The restoration of cell morphology may be an important application for rescuing the impaired dendritic development in MeCP2-deficient brains that we and others have observed [9]. The potential action of VPA in molecular transport, metabolism, and biochemistry is also very interesting because MeCP2 was recently found to play a role in RNA splicing [28], [29] and nuclear size determination [30]. In addition, as a next step, it would be interesting to explore the cell type-specific changes of some of the candidate genes we have discovered. "
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    ABSTRACT: Rett syndrome (RTT) is a devastating neurodevelopmental disorder that occurs once in every 10,000-15,000 live female births. Despite intensive research, no effective cure is yet available. Valproic acid (VPA) has been used widely to treat mood disorder, epilepsy, and a growing number of other disorders. In limited clinical studies, VPA has also been used to control seizure in RTT patients with promising albeit somewhat unclear efficacy. In this study we tested the effect of VPA on the neurological symptoms of RTT and discovered that short-term VPA treatment during the symptomatic period could reduce neurological symptoms in RTT mice. We found that VPA restores the expression of a subset of genes in RTT mouse brains, and these genes clustered in neurological disease and developmental disorder networks. Our data suggest that VPA could be used as a drug to alleviate RTT symptoms.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "One of the targets of MeCP2 is the brain-derived neurotrophic factor ( BNDF ) gene, whose protein is synthesized in response to neuronal activity and is essential for appropriate brain function. A recent work using ESCs has studied the maturation process of neurons and found that MeCP2 regulates not only BDNF levels but also the nuclear size and RNA synthesis during the process (Yazdani et al. 2012 ). Furthermore, RTT mutations in MECP2 have recently been described which abolish the interaction of MeCP2 with the NCoR/SMRT corepressor , a fi nding in line with the hypothesis that brain dysfunction in RTT is caused by a loss of the MeCP2 connection between the NCoR/SMRT corepressors and chromatin (Lyst et al. 2013 ). "
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    ABSTRACT: Neural differentiation is a complex process that requires highly accurate spatial and temporal regulation by extracellular and intracellular programs. Epigenetic mechanisms, such as DNA methylation, covalent histone posttranscriptional modifications, chromatin organization, and noncoding regulatory RNA, are key regulators of pluripotency maintenance and differentiation. The misregulation of these mechanisms could lead to neurological diseases and cancer. © 2014 Springer Science+Business Media New York. All rights are reserved.
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    • "mice (56). An MeCP2-related size dependence was also observed in embryonic stem cells by the same authors, and it has attributed to an increase in histone H1 on MeCP2 depletion (24,56). Similarly, neurons from the Mecp2tm1.1Bird "
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    ABSTRACT: MeCP2 is a methyl-CpG-binding protein that is a main component of brain chromatin in vertebrates. In vitro studies have determined that in addition to its specific methyl-CpG-binding domain (MBD) MeCP2 also has several chromatin association domains. However, the specific interactions of MeCP2 with methylated or non-methylated chromatin regions and the structural characteristics of the resulting DNA associations in vivo remain poorly understood. We analysed the role of the MBD in MeCP2-chromatin associations in vivo using an MeCP2 mutant Rett syndrome mouse model (Mecp2(tm)(1)(.)(1)(Jae)) in which exon 3 deletion results in an N-terminal truncation of the protein, including most of the MBD. Our results show that in mutant mice, the truncated form of MeCP2 (ΔMeCP2) is expressed in different regions of the brain and liver, albeit at 50% of its wild-type (wt) counterpart. In contrast to the punctate nuclear distribution characteristic of wt MeCP2, ΔMeCP2 exhibits both diffuse nuclear localization and a substantial retention in the cytoplasm, suggesting a dysfunction of nuclear transport. In mutant brain tissue, neuronal nuclei are smaller, and ΔMeCP2 chromatin is digested faster by nucleases, producing a characteristic nuclease-resistant dinucleosome. Although a fraction of ΔMeCP2 is found associated with nucleosomes, its interaction with chromatin is transient and weak. Thus, our results unequivocally demonstrate that in vivo the MBD of MeCP2 together with its adjacent region in the N-terminal domain are critical for the proper interaction of the protein with chromatin, which cannot be replaced by any other of its protein domains.
    Full-text · Article · Apr 2013 · Nucleic Acids Research
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