An AT-Hook Domain in MeCP2 Determines the Clinical Course of Rett Syndrome and Related Disorders

Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
Cell (Impact Factor: 32.24). 02/2013; 152(5):984-96. DOI: 10.1016/j.cell.2013.01.038
Source: PubMed


Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2's key functions is to alter chromatin structure.

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    • "Top: Comparison of hippocampus from Mecp2 1/y WT and male mice with a late truncating Mecp2 G273X mutation (Mecp2-G273X). See Baker et al. (2013) for details of mouse generation and phenotype; Middle: Comparison of amygdala from Mecp2 1/y and Mecp2 2/y mice. See Samaco et al. (2013); Bottom: Comparison of hypothalamus from Mecp2 1/y and Mecp2 2/y mice. "
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    ABSTRACT: Rett syndrome is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however behavioural and emotional symptoms also severely affect their quality of life. Here we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of Rett syndrome (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behaviour of the Mecp2(+/-) mice were found to be reversible with environmental enrichment from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of Rett syndrome is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating HPA-axis dysregulation. Environmental enrichment of Mecp2(+/-) mice normalised basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of Rett syndrome, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioural and cognitive dimensions, of this devastating neurodevelopmental disorder. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Developmental Neurobiology 05/2015; DOI:10.1002/dneu.22308 · 3.37 Impact Factor
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    • "Involvement of MECP2 in chromatin regulation and maintenance of global nuclear architecture is well documented [27,52,53]. In particular, it is known that MECP2 plays a role in the regulation of transcription, being mostly a transcriptional repressor [54-56] and also an activator [54]. "
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    ABSTRACT: BackgroundMethyl-CpG binding protein 2 (MECP2) is a protein that specifically binds methylated DNA, thus regulating transcription and chromatin organization. Mutations in the gene have been identified as the principal cause of Rett syndrome, a severe neurological disorder. Although the role of MECP2 has been extensively studied in nervous tissues, still very little is known about its function and cell type specific distribution in other tissues.ResultsUsing immunostaining on tissue cryosections, we characterized the distribution of MECP2 in 60 cell types of 16 mouse neuronal and non-neuronal tissues. We show that MECP2 is expressed at a very high level in all retinal neurons except rod photoreceptors. The onset of its expression during retina development coincides with massive synapse formation. In contrast to astroglia, retinal microglial cells lack MECP2, similar to microglia in the brain, cerebellum, and spinal cord. MECP2 is also present in almost all non-neural cell types, with the exception of intestinal epithelial cells, erythropoietic cells, and hair matrix keratinocytes. Our study demonstrates the role of MECP2 as a marker of the differentiated state in all studied cells other than oocytes and spermatogenic cells. MECP2-deficient male (Mecp2-/y ) mice show no apparent defects in the morphology and development of the retina. The nuclear architecture of retinal neurons is also unaffected as the degree of chromocenter fusion and the distribution of major histone modifications do not differ between Mecp2-/y and Mecp2 wt mice. Surprisingly, the absence of MECP2 is not compensated by other methyl-CpG binding proteins. On the contrary, their mRNA levels were downregulated in Mecp2-/y mice.ConclusionsMECP2 is almost universally expressed in all studied cell types with few exceptions, including microglia. MECP2 deficiency does not change the nuclear architecture and epigenetic landscape of retinal cells despite the missing compensatory expression of other methyl-CpG binding proteins. Furthermore, retinal development and morphology are also preserved in Mecp2-null mice. Our study reveals the significance of MECP2 function in cell differentiation and sets the basis for future investigations in this direction.
    Epigenetics & Chromatin 08/2014; 7(1):17. DOI:10.1186/1756-8935-7-17 · 5.33 Impact Factor
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    • "MeCP2 was a prime candidate for promoting ATRX binding because it associates directly with the ATRX protein (13) and it co-localizes with ATRX at the H19 ICR and Gtl2 DMR in the neonatal brain (24). Furthermore, MeCP2 is required in neurons for the localization of ATRX at DAPI-rich heterochromatin bundles in the nucleus (49,50). To test whether MeCP2 is required for ATRX binding to the ICR, we performed ChIP for ATRX in control and MeCP2-null forebrain. "
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    ABSTRACT: ATRX and MeCP2 belong to an expanding group of chromatin-associated proteins implicated in human neurodevelopmental disorders, although their gene-regulatory activities are not fully resolved. Loss of ATRX prevents full repression of an imprinted gene network in the postnatal brain and in this study we address the mechanistic aspects of this regulation. We show that ATRX binds many imprinted domains individually but that transient co-localization between imprinted domains in the nuclei of neurons does not require ATRX. We demonstrate that MeCP2 is required for ATRX recruitment and that deficiency of either ATRX or MeCP2 causes decreased frequency of long-range chromatin interactions associated with altered nucleosome density at CTCF-binding sites and reduced CTCF occupancy. These findings indicate that MeCP2 and ATRX regulate gene expression at a subset of imprinted domains by maintaining a nucleosome configuration conducive to CTCF binding and to the maintenance of higher order chromatin structure.
    Nucleic Acids Research 07/2014; 42(13). DOI:10.1093/nar/gku564 · 9.11 Impact Factor
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