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1.  Acetyl-L-Carnitine Improves Behavior and Dendritic Morphology in a Mouse Model of Rett Syndrome 
PLoS ONE  2012;7(12):e51586.
Rett syndrome (RTT) is a devastating neurodevelopmental disorder affecting 1 in 10,000 girls. Approximately 90% of cases are caused by spontaneous mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Girls with RTT suffer from severe motor, respiratory, cognitive and social abnomalities attributed to early deficits in synaptic connectivity which manifest in the adult as a myriad of physiological and anatomical abnormalities including, but not limited to, dimished dendritic complexity. Supplementation with acetyl-L-carnitine (ALC), an acetyl group donor, ameliorates motor and cognitive deficits in other disease models through a variety of mechanisms including altering patterns of histone acetylation resulting in changes in gene expression, and stimulating biosynthetic pathways such as acetylcholine. We hypothesized ALC treatment during critical periods in cortical development would promote normal synaptic maturation, and continuing treatment would improve behavioral deficits in the Mecp21lox mouse model of RTT. In this study, wildtype and Mecp21lox mutant mice received daily injections of ALC from birth until death (postnatal day 47). General health, motor, respiratory, and cognitive functions were assessed at several time points during symptom progression. ALC improved weight gain, grip strength, activity levels, prevented metabolic abnormalities and modestly improved cognitive function in Mecp2 null mice early in the course of treatment, but did not significantly improve motor or cognitive functions assessed later in life. ALC treatment from birth was associated with an almost complete rescue of hippocampal dendritic morphology abnormalities with no discernable side effects in the mutant mice. Therefore, ALC appears to be a promising therapeutic approach to treating early RTT symptoms and may be useful in combination with other therapies.
PMCID: PMC3515484  PMID: 23227269
2.  Age-dependent expression of MeCP2 in a heterozygous mosaic mouse model 
Human Molecular Genetics  2011;20(9):1834-1843.
Functional deficiency of the X-linked methyl-CPG binding protein 2 (MeCP2) leads to the neurodevelopmental disorder Rett syndrome (RTT). Due to random X-chromosome inactivation (XCI), most RTT patients are females who are heterozygous for the MECP2 mutation and therefore mosaic in MeCP2 deficiency. Some MECP2 heterozygote females are found to have unbalanced XCI, which may affect the severity of neurological symptoms seen in these patients; however, whether MeCP2 deficiency affects XCI in the postnatal and adult brain is unclear. Here we developed a novel MeCP2 mosaic mouse model in which the X chromosome containing the wild-type Mecp2 expresses a green fluorescent protein (GFP) transgene, while the X chromosome harboring the mutant Mecp2 does not. Due to random XCI, the neurons in the female MeCP2 mosaic mice express either wild-type MeCP2 (GFP+) or mutant MeCP2 (GFP−), and the two can be distinguished by GFP fluorescence. Using this mouse model, we evaluated XCI in female heterozygote mice from 3 to 9 months after birth. We found that MeCP2 deficiency does not affect XCI at 3 months of age, but does alter the proportion of wild-type MeCP2-expressing neurons at later ages, suggesting that MeCP2 impacts XCI patterns in an age-dependent manner. Given the important function of MeCP2 in neuronal development, our data could shed light on how MeCP2 deficiency affects postnatal brain functions and the dynamic changes in the neurological symptoms of RTT.
PMCID: PMC3071674  PMID: 21330301
3.  The relationship of Rett syndrome and MECP2 disorders to autism 
Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.
PMCID: PMC3513680  PMID: 23226951
Rett syndrome; autism; neurodevelopmental disorder; MECP2; clinical feature; treatment
4.  Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation 
Human Molecular Genetics  2011;20(11):2103-2115.
Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder that affects girls due primarily to mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). The majority of RTT patients carry missense and nonsense mutations leading to a hypomorphic MECP2, while null mutations leading to the complete absence of a functional protein are rare. MECP2 is an X-linked gene subject to random X-chromosome inactivation resulting in mosaic expression of mutant MECP2. The lack of human brain tissue motivates the need for alternative human cellular models to study RTT. Here we report the characterization of a MECP2 mutation in a classic female RTT patient involving rearrangements that remove exons 3 and 4 creating a functionally null mutation. To generate human neuron models of RTT, we isolated human induced pluripotent stem (hiPS) cells from RTT patient fibroblasts. RTT-hiPS cells retained the MECP2 mutation, are pluripotent and fully reprogrammed, and retained an inactive X-chromosome in a nonrandom pattern. Taking advantage of the latter characteristic, we obtained a pair of isogenic wild-type and mutant MECP2 expressing RTT-hiPS cell lines that retained this MECP2 expression pattern upon differentiation into neurons. Phenotypic analysis of mutant RTT-hiPS cell-derived neurons demonstrated a reduction in soma size compared with the isogenic control RTT-hiPS cell-derived neurons from the same RTT patient. Analysis of isogenic control and mutant hiPS cell-derived neurons represents a promising source for understanding the pathogenesis of RTT and the role of MECP2 in human neurons.
PMCID: PMC3090191  PMID: 21372149
5.  Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology 
Nature neuroscience  2009;12(3):311-317.
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 due to lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease, is unknown. Here, we show that loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brain. Using an in vitro co-culture system, we find that mutant astrocytes from a RTT mouse model, and their conditioned medium, fail to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that in RTT brain, astrocytes carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, likely due to aberrant secretion of soluble factor(s).
PMCID: PMC3134296  PMID: 19234456
6.  Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome 
PLoS ONE  2010;5(7):e11534.
Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2−/y).
Principal Findings
We found that EE delayed and attenuated some neurological alterations presented by Mecp2−/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models.
We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.
PMCID: PMC2902516  PMID: 20634955
7.  Rett Syndrome: Revised Diagnostic Criteria and Nomenclature 
Annals of neurology  2010;68(6):944-950.
Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials.
RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT.
The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed.
These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.
PMCID: PMC3058521  PMID: 21154482
8.  Exogenous Brain Derived Neurotrophic Factor Rescues Synaptic Dysfunction in Mecp2 Null Mice 
The Journal of Neuroscience  2010;30(15):5303-5310.
Postnatal deficits in Brain-Derived Neurotrophic Factor (BDNF) are thought to contribute to pathogenesis of Rett syndrome (RTT), a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 null mice, a model of RTT, BDNF deficits are most pronounced in structures important for autonomic and respiratory control, functions that are severely affected in RTT patients. However, relatively little is known about how these deficits affect neuronal function or how they may be linked to specific RTT endophenotypes. To approach these issues we analyzed synaptic function in the brainstem nucleus tractus solitarius (nTS), the principal site for integration of primary visceral afferent inputs to central autonomic pathways and a region in which we found markedly reduced levels of BDNF in Mecp2 mutants. Our results demonstrate that the amplitude of spontaneous miniature and evoked EPSCs in nTS neurons is significantly increased in Mecp2 null mice and, accordingly, that mutant cells are more likely than wildtype to fire action potentials in response to primary afferent stimulation. These changes occur without any increase in intrinsic neuronal excitability and are unaffected by blockade of inhibitory GABA currents. However, this synaptopathy is associated with decreased BDNF availability in the primary afferent pathway and can be rescued by application of exogenous BDNF. On the basis of these findings we hypothesize that altered sensory gating in nTS contributes to cardiorespiratory instability in RTT and that nTS is a site at which restoration of normal BDNF signaling could help reestablish normal homeostatic controls.
PMCID: PMC3367888  PMID: 20392952
cardiorespiratory; synapse; bdnf; nucleus tractus solitarius; glutamate; brainstem
Rett syndrome (RTT) is a neurodevelopmental disorder predominantly occurring in females with an incidence of 1:10,000 births and caused by sporadic mutations in the MECP2 gene, which encodes methyl-CpG-binding protein-2, an epigenetic transcription factor that binds methylated DNA. The clinical hallmarks include a period of apparently normal early development followed by a plateau and then subsequent frank regression. Impaired visual and aural contact often leads to an initial diagnosis of autism. The characterization of experimental models based on the loss-of-function of the mouse Mecp2 gene revealed that subtle changes in the morphology and function of brain cells and synapses have profound consequences on network activities that underlie critical brain functions. Furthermore, these experimental models have been used for successful reversals of RTT-like symptoms by genetic, pharmacological and environmental manipulations, raising hope for novel therapeutic strategies to improve the quality of life of RTT individuals.
PMCID: PMC3059199  PMID: 21239731
10.  Early intervention with psychostimulants or antidepressants to increase methyl-CpG-binding protein 2 (MeCP2) expressions: A potential therapy for Rett syndrome 
Rett syndrome (RTT) is a severe X-linked postnatal neurodevelopmental disorder. The syndrome is caused primarily by mutations in the methyl CpG binding protein 2 (MeCP2) gene on Xq28. Most individuals with RTT are female, and female RTT is normally heterozygous for mutations in MeCP2. Patients with RTT display a normal period of development prior to the onset of symptoms, at which point they undergo a period of regression. Currently, no effective medication is available for this disorder, although animal studies have suggested that RTT symptoms are potentially reversible. For females with RTT, the severity of symptoms and progression of the disease varies a great deal, despite its homogenous genetic origin. These differences could be attributed to differences in the mutation points of MeCP2 and the skew caused by X-chromosome inactivation. Thus, the increased expression in the normal MeCP2 gene could decrease the severity of the disease. Based on findings from studies on animals indicating that fluoxetine (an antidepressant) and cocaine (a psychostimulant) can increase MeCP2 expression in the brain, it is suggested that early intervention with antidepressants or psychostimulants could increase the normal MeCP2 expression in females with RTT, who are normally heterozygous. This therapeutic hypothesis could be tested in an RTT animal model. Following the identification of the antidepressants or psychostimulants with the greatest influence on MeCP2 expression, a combination of early detection of the disorder with early intervention may result in improved therapeutic outcomes. Furthermore, a trial investigating the effects of antidepressants or psychostimulants on MeCP2 expression in lymphocyte culture from patients with RTT is suggested for clinical therapeutic prediction.
PMCID: PMC3560675  PMID: 22207122
X-chromosome inactivation; methyl CpG binding protein 2 (MeCP2); psychostimulants; antidepressants; treatment; Rett syndrome
11.  Ocular MECP2 Protein Expression in Patients with and without Rett Syndrome 
Pediatric neurology  2010;43(1):35-40.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. MECP2 protein is primarily expressed in neurons, and mutations in the gene lead to the clinical features of RTT in human patients and neurological deficits in murine models. Visual function is relatively preserved in RTT patients, but the cause for this is unknown. We analyzed the eyes of two RTT patients who died of the disease, and found no gross or microscopic changes. MECP2 expression was examined using immunohistochemistry, and nuclear protein expression was largely limited to ganglion cells and the portion of the inner nuclear layer populated by amacrine cells. No significant differences in MECP2 protein level or distribution were identified in the two eyes from the RTT patients as compared to eleven controls. The findings were compared to MECP2 expression in the brain of these two subjects and in MeCP2 deficient mice. Our findings suggest that the normally limited expression of MECP2 in visual pathway neurons may underlie intact vision in RTT.
PMCID: PMC2916867  PMID: 20682201
12.  Dynamic changes in Histone H3 lysine 9 acetylation localization patterns during neuronal maturation require MeCP2 
Mutations within the gene encoding methyl CpG binding protein 2 (MECP2) cause the autism-spectrum neurodevelopmental disorder Rett Syndrome (RTT). MECP2 recruits histone deacetylase to methylated DNA and acts as a long-range regulator of methylated genes. Despite ubiquitous MECP2 expression, the phenotype of RTT and the Mecp2-deficient mouse is largely restricted to the postnatal brain. Since Mecp2-deficient mice have a defect in neuronal maturation, we sought to understand how MECP2/Mecp2 mutations globally affect histone modifications during postnatal brain development by an immunofluorescence approach. Using an antibody specific to acetylated histone H3 lysine 9 (H3K9ac), a bright punctate nuclear staining pattern was observed as MECP2 expression increased in early postnatal neuronal nuclei. As neurons matured in juvenile and adult brain samples, the intensity of H3K9ac staining was reduced. Mecp2-deficient mouse and RTT cerebral neurons lacked this developmental reduction in H3K9ac staining compared to age-matched controls, resulting in a significant increase in neuronal nuclei with bright H3K9ac punctate staining. In contrast, trimethylated histone H3 lysine 9 (H3K9me3) localized to heterochromatin independent of MeCP2, but showed significantly reduced levels in Mecp2 deficient mouse and RTT brain. Autism brain with reduced MECP2 expression displayed similar histone H3 alterations as RTT brain. These observations suggest that MeCP2 regulates global histone modifications during a critical postnatal stage of neuronal maturation. These results have implications for understanding the molecular pathogenesis of RTT and autism in which MECP2 mutation or deficiency corresponds with arrested neurodevelopment.
PMCID: PMC1857283  PMID: 17464364
histone; acetylation; methylation; MeCP2; Rett syndrome; autism; brain; neuron
13.  FOXG1-Related Disorders: From Clinical Description to Molecular Genetics 
Molecular Syndromology  2011;2(3-5):153-163.
Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mutations in loci other than MECP2 have also been found in individuals that have been labeled as atypical RTT. Among them, a mutation in the gene forkhead box G1 (FOXG1) has been involved in the molecular aetiology of the congenital variant of RTT. The FOXG1 gene encodes a winged-helix transcriptional repressor essential for the development of the ventral telencephalon in embryonic forebrain. Later, FOXG1 continues to be expressed in neurogenetic zones of the postnatal brain. Although RTT affects quasi-exclusively girls, FOXG1 mutations have also been identified in male patients. As far as we know, about 12 point mutations and 13 cases with FOXG1 molecular abnormalities (including translocation, duplication and large deletion on the chromosome 14q12) have been described in the literature. Affected individuals with FOXG1 mutations have shown dysmorphic features and Rett-like clinical course, including normal perinatal period, postnatal microcephaly, seizures and severe mental retardation. Interestingly, the existing animal models of FOXG1 deficiency showed similar phenotype, suggesting that animal models may be a fascinating model to understand this human disease. Here, we describe the impacts of FOXG1 mutations and their associated phenotypes in human and mouse models.
PMCID: PMC3366704  PMID: 22670136
Chromosome 14; Clinical features; Congenital variant; Encephalopathy; FOXG1; Human; Microcephaly; Molecular basis of disease; Mouse; Rett syndrome
14.  X-Chromosome Inactivation in Rett Syndrome Human Induced Pluripotent Stem Cells 
Rett syndrome (RTT) is a neurodevelopmental disorder that affects girls due primarily to heterozygous mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Random X-chromosome inactivation (XCI) results in cellular mosaicism in which some cells express wild-type (WT) MECP2 while other cells express mutant MECP2. The generation of patient-specific human induced pluripotent stem cells (hiPSCs) facilitates the production of RTT-hiPSC-derived neurons in vitro to investigate disease mechanisms and identify novel drug treatments. The generation of RTT-hiPSCs has been reported by many laboratories, however, the XCI status of RTT-hiPSCs has been inconsistent. Some report RTT-hiPSCs retain the inactive X-chromosome (post-XCI) of the founder somatic cell allowing isogenic RTT-hiPSCs that express only the WT or mutant MECP2 allele to be isolated from the same patient. Post-XCI RTT-hiPSCs-derived neurons retain this allele-specific expression pattern of WT or mutant MECP2. Conversely, others report RTT-hiPSCs in which the inactive X-chromosome of the founder somatic cell reactivates (pre-XCI) upon reprogramming into RTT-hiPSCs. Pre-XCI RTT-hiPSC-derived neurons exhibit random XCI resulting in cellular mosaicism with respect to WT and mutant MECP2 expression. Here we review and attempt to interpret the inconsistencies in XCI status of RTT-hiPSCs generated to date by comparison to other pluripotent systems in vitro and in vivo and the methods used to analyze XCI. Finally, we discuss the relative strengths and weaknesses of post- and pre-XCI hiPSCs in the context of RTT, and other X-linked and autosomal disorders for translational medicine.
PMCID: PMC3311266  PMID: 22470355
Rett syndrome; human induced pluripotent stem cells; X-chromosome inactivation
15.  Female Mecp2+/− mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies 
Human Molecular Genetics  2012;22(1):96-109.
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2+/− mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2+/− mice, we analyzed Mecp2+/− mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2+/− mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2+/− mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT.
PMCID: PMC3522402  PMID: 23026749
16.  Effects of ω-3 Polyunsaturated Fatty Acids on Plasma Proteome in Rett Syndrome 
Mediators of Inflammation  2013;2013:723269.
The mechanism of action of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS) alterations following ω-3 PUFAs supplementation in patients with Rett syndrome (RTT), a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2) protein. Here, we tested the hypothesis that ω-3 PUFAs may modify the plasma proteome profile in typical RTT patients with MECP2 mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented with ω-3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR), was changed at the baseline in the untreated patients. Following ω-3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62%) proteins being normalized. ω-3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.
PMCID: PMC3872159  PMID: 24385686
Neurobiology of disease  2009;35(2):219-233.
Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing (∼twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48hrs of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96hrs was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spines density than controls after 96hrs of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96hrs of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT-associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction.
PMCID: PMC2722110  PMID: 19442733
MeCP2; Rett syndrome; dendrite; dendritic spine; pyramidal neuron; hippocampus; DiOlistics; human postmortem brain
18.  A brain-derived MeCP2 complex supports a role for MeCP2 in RNA processing 
Bioscience reports  2011;31(5):333-343.
Mutations in MECP2 (methyl CpG binding protein 2) are linked to the severe postnatal neurodevelopmental disorder Rett Syndrome (RTT). MeCP2 was originally characterized as a transcriptional repressor that preferentially bound methylated DNA, however, recent data indicates MeCP2 is a multifunctional protein. MeCP2 binding is now associated with certain expressed genes and involved in nuclear organization as well, indicating its gene regulatory function is context dependent. In addition, MeCP2 is proposed to regulate mRNA splicing and a mouse model for RTT shows aberrant mRNA splicing. To further understand MeCP2 and potential roles in RTT pathogenesis, we have employed a biochemical approach to identify the MeCP2 protein complexes present in the mammalian brain. We show that MeCP2 exists in at least four biochemically distinct pools in the brain and characterize one novel brain-derived MeCP2 complex that contains the splicing factor Prpf3. MeCP2 directly interacts with Prpf3 in vitro and in vivo and many MECP2 RTT truncations disrupt the MeCP2-Prpf3 complex. In addition, MeCP2 and Prpf3 associate in vivo with mRNAs from genes known to be expressed when their promoters are associated with MeCP2. This data supports a role for MeCP2 in mRNA biogenesis and suggests an additional mechanism for RTT pathophysiology.
PMCID: PMC3148018  PMID: 21070191
MeCP2; Prpf3; Rett Syndrome; RNA
19.  A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome 
Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α–tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.
PMCID: PMC3945638  PMID: 24639629
Rett syndrome; dense core vesicle; activity-dependent BDNF release; Tubastatin-A; tubulin acetylation
20.  Isogenic Pairs of Wild Type and Mutant Induced Pluripotent Stem Cell (iPSC) Lines from Rett Syndrome Patients as In Vitro Disease Model 
PLoS ONE  2011;6(9):e25255.
Rett syndrome (RTT) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5–6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology.
PMCID: PMC3180386  PMID: 21966470
21.  Experience-Dependent Retinogeniculate Synapse Remodeling is Abnormal in MeCP2 deficient mice 
Neuron  2011;70(1):35-42.
Mutations in MECP2 underlie the neurodevelopmental disorder Rett (RTT) syndrome. One hallmark of RTT is relatively normal development followed by a later onset of symptoms. Growing evidence suggests an etiology of disrupted synaptic function, yet it is unclear how these abnormalities explain the clinical presentation of RTT. Here we investigate synapse maturation in Mecp2-deficient mice at a circuit with distinct developmental phases– the retinogeniculate synapse. We find that synapse development in mutants is comparable to that of WT littermates between postnatal days 9–21, indicating that initial phases of synapse formation, elimination and strengthening are not significantly affected by MeCP2 absence. However, during the subsequent experience-dependent phase of synapse remodeling, the circuit becomes abnormal in mutants as retinal innervation of relay neurons increases and retinal inputs fail to strengthen further. Moreover, synaptic plasticity in response to visual deprivation is disrupted in mutants. These results suggest a crucial role for Mecp2 in experience-dependent refinement of synaptic circuits.
PMCID: PMC3082316  PMID: 21482354
22.  Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation 
Mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2), cause most cases of Rett syndrome (RTT), an X-linked neurodevelopmental disorder. Both RTT and autism are “pervasive developmental disorders” and share a loss of social, cognitive and language skills and a gain in repetitive stereotyped behavior, following apparently normal perinatal development. Although MECP2 coding mutations are a rare cause of autism, MeCP2 expression defects were previously found in autism brain. To further study the role of MeCP2 in autism spectrum disorders (ASDs), we determined the frequency of MeCP2 expression defects in brain samples from autism and other ASDs. We also tested the hypotheses that MECP2 promoter mutations or aberrant promoter methylation correlate with reduced expression in cases of idiopathic autism. MeCP2 immunofluorescence in autism and other neurodevelopmental disorders was quantified by laser scanning cytometry and compared with control postmortem cerebral cortex samples on a large tissue microarray. A significant reduction in MeCP2 expression compared to age-matched controls was found in 11/14 autism (79%), 9/9 RTT (100%), 4/4 Angelman syndrome (100%), 3/4 Prader-Willi syndrome (75%), 3/5 Down syndrome (60%), and 2/2 attention deficit hyperactivity disorder (100%) frontal cortex samples. One autism female was heterozygous for a rare MECP2 promoter variant that correlated with reduced MeCP2 expression. A more frequent occurrence was significantly increased MECP2 promoter methylation in autism male frontal cortex compared to controls. Furthermore, percent promoter methylation of MECP2 significantly correlated with reduced MeCP2 protein expression. These results suggest that both genetic and epigenetic defects lead to reduced MeCP2 expression and may be important in the complex etiology of autism.
PMCID: PMC1866172  PMID: 17486179
autism; DNA methylation; Rett syndrome; neurodevelopmental disorders; MeCP2
23.  Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome 
Molecular and Cellular Biology  2006;26(13):5033-5042.
Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.
PMCID: PMC1489175  PMID: 16782889
24.  Mecp2 organizes juvenile social behavior in a sex-specific manner 
Methyl-CpG-binding protein 2 (MeCP2) binds methylated DNA and recruits co-repressor proteins to modify chromatin and alter gene transcription. Mutations of the MECP2 gene can cause Rett syndrome (RTT), while subtle reductions of MeCP2 expression may be associated with male dominated social and neurodevelopmental disorders. We report that transiently decreased amygdala Mecp2 expression during a sensitive period of brain sexual differentiation disrupts the organization of sex differences in juvenile social play behavior. Interestingly, neonatal treatment with Mecp2 siRNA within the developing amygdala reduced juvenile social play behavior in males but not females. Reduced Mecp2 expression did not change juvenile sociability or anxiety-like behavior, suggesting this disruption is associated with subtle behavioral modification. This suggests Mecp2 may have an overlooked role in the organization of sexually dimorphic behaviors and that male juvenile behavior is particularly sensitive to Mecp2 disruption during this period of development.
PMCID: PMC2569867  PMID: 18614683
Mecp2; siRNA; amygdala; sex-difference; behavior; epigenetic
25.  The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity 
Neuropsychopharmacology  2012;38(1):212-219.
Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator of gene expression that is an important epigenetic factor in the maintenance and development of the central nervous system. The neurodevelopmental disorders Rett syndrome and MECP2 duplication syndrome arise from loss-of-function and gain-of-function alterations in MeCP2 expression, respectively. Several animal models have been developed to recapitulate the symptoms of Rett syndrome and MECP2 duplication syndrome. Cell morphology, neurotransmission, and cellular processes that support learning and memory are compromised as a result of MeCP2 loss- or gain-of-function. Interestingly, loss-of-MeCP2 function and MeCP2 overexpression trigger diametrically opposite changes in synaptic transmission. These findings indicate that the precise regulation of MeCP2 expression is a key requirement for the maintenance of synaptic and neuronal homeostasis and underscore its importance in central nervous system function. This review highlights the functional role of MeCP2 in the brain as a regulator of synaptic and neuronal plasticity as well as its etiological role in the development of Rett syndrome and MECP2 duplication syndrome.
PMCID: PMC3521965  PMID: 22781840
MeCP2 duplication syndrome; behavior; long-term potentiation; synaptic transmission; Rett syndrome; animal models; glutamate; molecular and cellular neurobiology; neurodevelopment; neurophysiology

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