Methyl CpG Binding Protein 2 Duplication Research Articles

Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.

Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.

Sensory experiences questionnaire unravels differences in sensory profiles between MECP2-related disorders.

The methyl CpG-binding protein-2 (MECP2) gene is located on the Xq28 region. Loss of function mutations or increased copies of MECP2 result in Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. Individuals with both disorders exhibit overlapping autism symptoms, yet few studies have dissected the differences between these gene dosage sensitive disorders. Further, research examining sensory processing patterns in persons with RTT and MDS is largely absent. Thus, the goal of this study was to analyze and compare sensory processing patterns in persons with RTT and MDS. Towards this goal, caregivers of 50 female individuals with RTT and 122 male individuals with MDS, between 1 and 46 years of age, completed a standardized measure of sensory processing, the Sensory Experiences Questionnaire. Patterns detected in both disorders were compared against each other and against normative values. We found sensory processing abnormalities for both hyper- and hypo-sensitivity in both groups. Interestingly, abnormalities in MDS were more pronounced compared with in RTT, particularly with items concerning hypersensitivity and sensory seeking, but not hyposensitivity. Individuals with MDS also exhibited greater sensory symptoms compared with RTT in the areas of tactile and vestibular sensory processing and for both social and nonsocial stimuli. This study provides a first description of sensory symptoms in individuals with RTT and individuals with MDS. Similar to other neurodevelopmental disorders, a variety of sensory processing abnormalities was found. These findings reveal a first insight into sensory processing abnormalities caused by a dosage sensitive gene and may ultimately help guide therapeutic approaches for these disorders.

Genetic analysis of a pedigree with MECP2 duplication syndrome in China

BackgroundMECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder that primarily affects males. It is characterized by delayed or absent speech development, severe motor and cognitive impairment, and recurrent respiratory infections. MDS is caused by the duplication of a chromosomal region located on chromosome Xq28, which contains the methyl CpG binding protein-2 (MECP2) gene. MECP2 functions as a transcriptional repressor or activator, regulating genes associated with nervous system development. The objective of this study is to provide a clinical description of MDS, including imaging changes observed from the fetal period to the neonatal period.MethodsConventional G-banding was employed to analyze the chromosome karyotypes of all pedigrees under investigation. Subsequently, whole exome sequencing (WES), advanced biological information analysis, and pedigree validation were conducted, which were further confirmed by copy number variation sequencing (CNV-seq).ResultsChromosome karyotype analysis revealed that a male patient had a chromosome karyotype of 46,Y,dup(X)(q27.2q28). Whole-exon duplication in the MECP2 gene was revealed through WES results. CNV-seq validation confirmed the presence of Xq27.1q28 duplicates spanning 14.45 Mb, which was inherited from a mild phenotype mother. Neither the father nor the mother's younger brother carried this duplication.ConclusionIn this study, we examined a male child in a family who exhibited developmental delay and recurrent respiratory tract infections as the main symptoms. We conducted thorough family investigations and genetic testing to determine the underlying causes of the disease. Our findings will aid in early diagnosis, genetic counseling for male patients in this family, as well as providing prenatal diagnosis and reproductive guidance for female carriers.

How Families Manage the Complex Medical Needs of Their Children with MECP2 Duplication Syndrome.

MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder resulting from the duplication of the methyl-CpG-binding protein 2 (MECP2) gene. The clinical features of MDS include severe intellectual disability, global developmental delay, seizures, recurrent respiratory infections, and gastrointestinal problems. The aim of this qualitative study was to explore how the parents of children with MDS manage their child's seizures, recurrent respiratory infections, and gastrointestinal symptoms, and the impact on them as parents. The data were coded into three categories: (1) complex care needs in the home, (2) highly skilled caregivers, and (3) impact on caregivers and families. Complex 24 h care was required and parents developed complex skillsets to ensure that this was delivered well to their child. The provision of extensive complex medical care in the home had an impact on parent mental and physical health, family dynamics, and finances. This study captures the management of high-burden comorbidities in MDS at home. Investigations into how best to support caregiver wellbeing to reduce their stresses, whilst maintaining optimal child health and wellbeing, are needed.

Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives.

Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication of the MECP2 gene leads, mainly in boys, to the MECP2 duplication syndrome (MDS). No cure is currently available for MECP2 related disorders. However, several studies have reported that by re-expressing the wild-type gene is possible to restore defective phenotypes of Mecp2 null animals. This proof of principle endorsed many laboratories to search for novel therapeutic strategies to cure RTT. Besides pharmacological approaches aimed at modulating MeCP2-downstream pathways, genetic targeting of MECP2 or its transcript have been largely proposed. Remarkably, two studies focused on augmentative gene therapy were recently approved for clinical trials. Both use molecular strategies to well-control gene dosage. Notably, the recent development of genome editing technologies has opened an alternative way to specifically target MECP2 without altering its physiological levels. Other attractive approaches exclusively applicable for nonsense mutations are the translational read-through (TR) and t-RNA suppressor therapy. Reactivation of the MECP2 locus on the silent X chromosome represents another valid choice for the disease. In this article, we intend to review the most recent genetic interventions for the treatment of RTT, describing the current state of the art, and the related advantages and concerns. We will also discuss the possible application of other advanced therapies, based on molecular delivery through nanoparticles, already proposed for other neurological disorders but still not tested in RTT.

Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome

BackgroundX-linked methyl-CpG-binding protein 2 (MECP2) duplication syndrome is prevalent in approximately 1% of X-linked intellectual disabilities. Accumulating evidence has suggested that MECP2 is the causative gene of MECP2 duplication syndrome. We report a case of a 17-year-old boy with a 1.2 Mb duplication distal to MECP2 on chromosome Xq28. Although this region does not contain MECP2, the clinical features and course of the boy are remarkably similar to those observed in MECP2 duplication syndrome. Recently, case reports have described duplication in the region distal to, and not containing, MECP2. These regions have been classified as the K/L-mediated Xq28 duplication region and int22h1/int22h2-mediated Xq28 duplication region.The case reports also described signs similar to those of MECP2 duplication syndrome. To the best of our knowledge, ours is the first case to include these two regions.Case presentationThe boy presented with a mild to moderate regressive intellectual disability and progressive neurological disorder. He developed epilepsy at the age of 6 years and underwent a bilateral equinus foot surgery at 14 years of age because of the increasing spasticity in lower extremities since the age of 11. Intracranial findings showed hypoplasia of the corpus callosum, cerebellum, and brain stem; linear hyperintensity in the deep white matter; and decreased white matter capacity. During his childhood, he suffered from recurrent infection. However, genital problems, skin abnormalities and gastrointestinal manifestations (gastroesophageal reflux) were not observed.ConclusionsCases in which duplication was observed in the region of Xq28 that does not include MECP2 also showed symptoms similar to those of MECP2 duplication syndrome. We compared four pathologies: MECP2 duplication syndrome with minimal regions, duplication within the two distal regions without MECP2, and our case including both regions. Our results suggest that MECP2 alone may not explain all symptoms of duplication in the distal part of Xq28.

MECP2 duplication syndrome initially misdiagnosed as cerebral palsy: a case report.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene were first described as a cause of Rett syndrome. MECP2 duplication can cause intellectual disability, developmental delay, severe feeding difficulties, and recurrent infections. Here, we report a Korean family with MECP2 duplication syndrome, which was previously misdiagnosed as cerebral palsy. A man in his early 30 s visited our clinic with intellectual disability, speech impairment, epilepsy, and progressive spasticity. He had been previously misdiagnosed with cerebral palsy, and had received orthopedic surgeries such as musculotendinous lengthening and derotational osteotomy. After the surgeries, he received comprehensive rehabilitation. Upon carefully checking his family history, we noted that his younger brother had similar symptoms. Next-generation sequencing revealed whole exon duplication in MECP2 in both the patient and his brother; their mother also had this genetic mutation but was asymptomatic. Early diagnosis is essential for improving the success of MECP2 duplication syndrome treatment. Individuals with MECP2 duplication syndrome should be referred to specialists to manage multidisciplinary symptoms and to regularly check for complications that are common in this syndrome.

Surgery for foot deformities in MECP2 disorders: prevalence and risk factors.

Foot deformities in methyl-CpG binding protein 2 (MECP2) disorders are thought to be common, but reports are scant. The purpose of this study was to report the prevalence and type of foot deformities and surgical management for MECP2 disorders. In this retrospective, comparative study, all children presenting between June 2005 and July 2020, with a genetically confirmed MECP2-related disorder, were included. The primary outcome measure was the prevalence of surgery for foot deformities. Secondary outcomes included type and frequency of foot surgeries, age at surgery, ambulatory status, genetic severity, presence of scoliosis/hip displacement, seizures, and associated comorbidities. Chi-square testing was utilized for the analysis of risk factors. Fifty-six patients (Rett syndrome: N = 52, MECP2 duplication syndrome: N = 4; 93% female) met the inclusion criteria. The mean age at first presentation to orthopedics was 7.3 (SD, 3.9) years, with a final follow-up of 4.5 (SD, 4.9) years. Seven (13%) patients developed foot deformities, most commonly equinus or equinovarus (five patients, 71%), requiring surgical management. The remaining two patients had calcaneovalgus. The most common surgical procedure was Achilles tendon lengthening, followed by triple arthrodesis, at a mean age of 15.9 (range: 11.4-20.1) years. Hip displacement ( P = 0.04), need for hip surgery ( P = 0.001) and clinically relevant scoliosis ( P = 0.04) were significant risk factors for the development of symptomatic foot deformities. Although not as prevalent as scoliosis or hip displacement, foot deformities are still relatively common in MECP2 disorders, often necessitating surgical intervention to improve brace tolerance. Level of evidence: Level III - a retrospective comparative study.

Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage.

Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2), which encodes the MeCP2 protein. RTT is a MECP2-related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2. Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2-related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype-phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.

Gene Editing and Rett Syndrome: Does It Make the Cut?

Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 (MECP2) gene. The RTT is characterized by apparent normal early development followed by regression of communicative and fine motor skills. Comorbidities include epilepsy, severe cognitive impairment, and autonomic and motor dysfunction. Despite almost 60 clinical trials and the promise of a gene therapy, no cure has yet emerged with treatment remaining symptomatic. Advances in understanding RTT has provided insight into the complexity and exquisite control of MECP2 expression, where loss of expression leads to RTT and overexpression leads to MECP2 duplication syndrome. Therapy development requires regulated expression that matches the spatiotemporal endogenous expression of MECP2 in the brain. Gene editing has revolutionized gene therapy and promises an exciting strategy for many incurable monogenic disorders, including RTT, by editing the native locus and retaining endogenous gene expression. Here, we review the literature on the currently available editing technologies and discuss their limitations and applicability to the treatment of RTT.

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review.

Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with a ratio of 1:10.000. De novo mutations in the Methyl-CpG Binding protein 2 (MECP2) gene on the long arm of X chromosome are responsible for more than 95% cases of classical Rett. In the remaining cases (atypical Rett), other genes are involved such as the cyclin-dependent kinase-like 5 (CDKL5) and the forkhead box G1 (FOXG1). Duplications of the MECP2 locus cause MECP2 duplication syndrome (MDS) which concerns about 1% of male patients with intellectual disability. Sleep disorders are common in individuals with intellectual disability, while the prevalence in children is between 16 and 42%. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first 7 years of life and some degree of variability in correlation to age and genotype. Abnormalities in circadian rhythm and loss of glutamate homeostasis play a key role in the development of these disorders. Sleep disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). Sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with epilepsy, regression and others. Sleep dysfunction and epilepsy are deeply linked. Sleep deprivation could be an aggravating factor of epilepsy and anti-comitial therapy could interfere in sleep structure. Epilepsy prevalence in atypical Rett syndrome with severe clinical phenotype is higher than in classical Rett syndrome. However, RTT present a significant lifetime risk of epilepsy too. Sleep disturbances impact on child's development and patients' families and the evidence for its management is still limited. The aim of this review is to analyze pathophysiology, clinical features, the impact on other comorbidities and the management of sleep disorders in Rett syndrome and Rett-related syndrome.

MeCP2 duplication causes hyperandrogenism by upregulating LHCGR and downregulating ROR\u03b1

Duplication of MECP2 (methyl-CpG-binding protein 2) gene causes a serious neurological and developmental disorder called MECP2 duplication syndrome (MDS), which is usually found in males. A previous clinical study reported that MDS patient has precocious puberty with hyperandrogenism, suggesting increased MeCP2 may cause male hyperandrogenism. Here we use an MDS mouse model and confirm that MECP2 duplication significantly upregulates androgen levels. We show for the first time that MeCP2 is highly expressed in the Leydig cells of testis, where androgen is synthesized. Mechanistically, MECP2 duplication increases androgen synthesis and decreases androgen to estrogen conversion through either the upregulation of luteinizing hormone receptor (LHCGR) in testis, as a result of MeCP2 binds to G-quadruplex structure of Lhcgr promoter and recruits the transcription activator CREB1 or the downregulation of the expression of aromatase in testis by binding the CpG island of Rorα, an upstream regulator of aromatase. Taken together, we demonstrate that MeCP2 plays an important role in androgen synthesis, supporting a novel non-CNS function of MeCP2 in the process of sex hormone synthesis.

MECP2-Related Disorders in Males.

Methyl CpG binding protein 2 (MECP2) is located at Xq28 and is a multifunctional gene with ubiquitous expression. Loss-of-function mutations in MECP2 are associated with Rett syndrome (RTT), which is a well-characterized disorder that affects mainly females. In boys, however, mutations in MECP2 can generate a wide spectrum of clinical presentations that range from mild intellectual impairment to severe neonatal encephalopathy and premature death. Thus, males can be more difficult to classify and diagnose than classical RTT females. In addition, there are some variants of unknown significance in MECP2, which further complicate the diagnosis of these children. Conversely, the entire duplication of the MECP2 gene is related to MECP2 duplication syndrome (MDS). Unlike in RTT, in MDS, males are predominantly affected. Usually, the duplication is inherited from an apparently asymptomatic carrier mother. Both syndromes share some characteristics, but also differ in some aspects regarding the clinical picture and evolution. In the following review, we present a thorough description of the different types of MECP2 variants and alterations that can be found in males, and explore several genotype–phenotype correlations, although there is still a lot to understand.

MECP2 and the biology of MECP2 duplication syndrome.

MECP2duplication syndrome (MDS), a rare X-linked genomic disorder affecting predominantly males, is caused by duplication of the chromosomal region containing themethyl CpG binding protein-2 (MECP2)gene, which encodes methyl-CpG-binding protein 2 (MECP2), a multi-functional protein required for proper brain development and maintenance of brain function during adulthood. Disease symptoms include severe motor and cognitive impairment, delayed or absent speech development, autistic features, seizures, ataxia, recurrent respiratory infections, and shortened lifespan. The cellular and molecular mechanisms by which a relatively modest increase in MECP2 protein causes such severe disease symptoms are poorly understood and consequently there are no treatments available for this fatal disorder. This review summarizes what is known to date about the structure and zcomplex regulation of MECP2 and its many functions in the developing and adult brain. Additionally, recent experimental findings on the cellular and molecular underpinnings of MDS based on cell culture and mouse models of the disorder are reviewed. The emerging picture from these studies is that MDS is a neurodegenerative disorder in which neurons die in specific parts of the central nervous system, including the cortex, hippocampus, cerebellum, and spinal cord. Neuronal death likely results from astrocytic dysfunction, including a breakdown of glutamate homeostatic mechanisms. The role of elevations in the expression of glial acidic fibrillary protein (GFAP) in astrocytes and the microtubule-associated protein, Tau, in neurons to the pathogenesis of MDS is discussed. Lastly, potential therapeutic strategies to potentially treat MDS are discussed.

Hip Displacement in MECP2 Disorders: Prevalence and Risk Factors.

Methyl-CpG binding protein 2 (MECP2) disorders, including Rett syndrome and MECP2 duplication syndrome, are typified by profound intellectual disability, spasticity, and decline in gross motor function. Unlike scoliosis, linked to disease severity, little has been reported regarding the hip. The aim of this study was to report the prevalence and risk factors of hip displacement (HD) in MECP2 disorders. This was a retrospective, comparative study. Children with a genetically confirmed MECP2 disorder were included. The primary outcome measure was the prevalence of HD (migration percentage>30%). Secondary outcomes included age at HD onset, ambulatory status, presence of clinically relevant scoliosis, genetic severity, presence of seizures, and associated comorbidities. Analysis of proportions of categorical variables was performed using χ2 testing (P=0.05). Fifty-six patients (54 Rett syndrome and 2 MECP2 duplication syndrome), diagnosed at 6.6 (SD: 4.7) years, met the inclusion criteria. The prevalence of HD was 36% [onset, 7.7 (SD: 3.8) y]. Risk factors for HD were nonwalker status (P=0.04), scoliosis (P=0.001), and refractory epilepsy (P=0.04). The prevalence of HD in MECP2 disorders is comparable to cerebral palsy, associated with proxy measures of disease severity. These results can be used to develop hip surveillance programs for MECP2 disorders, allowing for timely management. Level III.

Influence of the disordered domain structure of MeCP2 on its structural stability and dsDNA interaction

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-associated structural protein. MeCP2 deregulation results in two neurodevelopmental disorders: MeCP2 dysfunction is associated with Rett syndrome, while excess of activity is associated with MeCP2 duplication syndrome. MeCP2 is an intrinsically disordered protein (IDP) constituted by six structural domains with variable, small percentage of well-defined secondary structure. Two domains, methyl-CpG binding domain (MBD) and transcription repressor domain (TRD), are the elements responsible for dsDNA binding ability and recruitment of the gene transcription/silencing machinery, respectively. Previously we studied the influence of the completely disordered, MBD-flanking domains (N-terminal domain, NTD, and intervening domain, ID) on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41,635). Here we report the biophysical study of the influence of the remaining domains (transcriptional repressor domain, TRD, and C-terminal domains, CTDα and CTDβ) on the structural stability of MBD and the dsDNA binding capabilities of MBD and ID. The influence of distant disordered domains on MBD properties makes it necessary to consider the NTD-MBD-ID variant as the minimal protein construct for studying dsDNA/chromatin binding properties, while the full-length protein should be considered for transcriptional regulation studies.

MeCP2: A Critical Regulator of Chromatin in Neurodevelopment and Adult Brain Function.

Methyl CpG binding protein 2 (MeCP2) was first identified as a nuclear protein with a transcriptional repressor role that recognizes DNA methylation marks. MeCP2 has a well-established function in neurodevelopment, as evidenced by the severe neurological impairments characteristic of the Rett syndrome (RTT) pathology and the MeCP2 duplication syndrome (MDS), caused by loss or gain of MeCP2 function, respectively. Research aimed at the underlying pathophysiological mechanisms of RTT and MDS has significantly advanced our understanding of MeCP2 functions in the nervous system. It has revealed, however, that MeCP2 has more varied and complex roles than previously thought. Here we review recent insights into the functions of MeCP2 in neurodevelopment and the less explored requirement for MeCP2 in adult brain function. We focus on the emerging view that MeCP2 is a global chromatin organizer. Finally, we discuss how the individual functions of MeCP2 in neurodevelopment and adulthood are linked to its role as a chromatin regulator.

Atypical Response Properties of the Auditory Cortex of Awake MECP2-Overexpressing Mice.

Methyl-CpG binding protein 2 (MECP2) is a gene associated with DNA methylation and has been found to be important for maintaining brain function. In humans, overexpression of MECP2 can cause a severe developmental disorder known as MECP2 duplication syndrome. However, it is still unclear whether MECP2 overexpression also causes auditory abnormalities, which are common in people with autism. MECP2-TG is a mouse model of MECP2 duplication syndrome and has been widely used for research on social difficulty and other autism-like disorders. In this study, we used a combination of multiple electrophysiological techniques to document the response properties of the auditory cortex of awake MECP2-TG mice. Our results showed that while the auditory brainstem responses are similar, cortical activity patterns including local field potentials (LFPs), multiunit activity (MUA), and single-neuron responses differ between MECP2-TG and wild-type (WT) mice. At the single-neuron level, the spike waveform of fast-spiking (FS) neurons from MECP2-TG mice is different from that of WT mice, as reflected by reduced peak/trough ratios in the transgenic mice. Both regular-spiking (RS) and FS neurons exhibited atypical response properties in MECP2-TG mice compared with WT mice, such as prolonged latency and an elevated intensity threshold; furthermore, regarding the response strength to different stimuli, MECP2-TG mice exhibited stronger responses to noise than to pure tone, while this pattern was not observed in WT mice. Our findings suggest that MECP2 overexpression can cause the auditory cortex to have atypical response properties, an implication that could be helpful for further understanding the nature of auditory deficits in autism.

MicroRNA-197 controls ADAM10 expression to mediate MeCP2\u2019s role in the differentiation of neuronal progenitors

Duplication of MECP2 (Methyl-CpG-binding protein 2) causes severe mental illness called MECP2 duplication syndrome (MDS), yet the underlying mechanism remains elusive. Here we show, in Tg(MECP2) transgenic mouse brain or cultured neural progenitor cells (NPCs), that elevated MeCP2 expression promotes NPC differentiation into neurons. Ectopic expression of MeCP2 inhibits ADAM10 and thus the NOTCH pathway during NPC differentiation. In human cells, this downregulation on ADAM10 was mediated by miRNA-197, which is upregulated by MeCP2. Surprisingly, miR-197 binds to the ADAM10 3′-UTR via its 3′ side, not the canonical seed sequence on the 5′ side. In mouse cells, a noncoding RNA Gm28836 is used to replace the function of miR-197 between MeCP2 and ADAM10. Similar to MeCP2, overexpressing miR-197 also promotes NPCs differentiation into neurons. Interestingly, three rare missense mutations (H371R, E394K, and G428S) in MECP2, which we identified in a Han Chinese autism spectrum disorders (ASD) cohort showed loss-of-function effects in NPC differentiation assay. These mutations cannot upregulate miR-197. Overexpressing miR-197 together with these MeCP2 mutations could rescue the downregulation on ADAM10. Not only the inhibitor of miR-197 could reverse the effect of overexpressed MeCP2 on NPCs differentiation, but also overexpression of miR-197 could reverse the NPCs differentiation defects caused by MECP2 mutations. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for NPC differentiation, which is affected by both MeCP2 duplication and mutation.

Experience-dependent MeCP2 expression in the excitatory cells of mouse visual thalamus.

Loss or gain of copy number of the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2) leads to neurodevelopmental disorders (Rett and MeCP2 duplication syndrome), indicating that precisely regulated MeCP2 expression during development is critical for mental health. Consistent with this idea, MeCP2 null mutants exhibit synaptic regression in the dorsal lateral geniculate nucleus (dLGN), the visual relay center in the thalamus, a phenotype resembling that of animals reared in the dark during the visual sensitive period. It remains unclear how MeCP2 expression is regulated during circuit formation and maturation, especially in excitatory and inhibitory populations of neurons. We found that, concomitant with the initiation of the dark-rearing sensitive period, MeCP2 protein levels were elevated in glutamatergic but not GABAergic neurons of the dLGN. Moreover, MeCP2 expression in glutamatergic populations was selectively reduced by dark-rearing. Therefore, we propose that visual experience–dependent MeCP2 induction in glutamatergic populations is essential for synaptic maturation within the dLGN.