scholarly journals Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kari Neier ◽  
Tianna E. Grant ◽  
Rebecca L. Palmer ◽  
Demario Chappell ◽  
Sophia M. Hakam ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Progression ◽  
Rett Syndrome ◽  
Gut Microbiome ◽  
Neurodevelopmental Disorder ◽  
Molecular Pathways ◽  
Linked Gene ◽  
Disease Phenotypes ◽  
Altered Metabolism ◽  
Inflammatory Profile

AbstractRett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

scholarly journals Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

2021 ◽  
Author(s):  
Kari Neier ◽  
Tianna Grant ◽  
Rebecca Palmer ◽  
Demario Chappell ◽  
Sophia Hakam ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Progression ◽  
Rett Syndrome ◽  
Gut Microbiome ◽  
Progressive Disease ◽  
Neurodevelopmental Disorder ◽  
Linked Gene ◽  
Disease Phenotypes ◽  
Gut Dysbiosis ◽  
Altered Metabolism

Abstract Rett syndrome (RTT) is a severe regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 knockout rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolite alterations in Mecp2e1 mutant females occurred prior to onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities, including those belonging to Clostridia, that were more consistent with RTT patients than males. These findings suggest new potential therapeutic targets for RTT and demonstrate the importance of further study in female animal models.

scholarly journals Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kerstin Ure ◽  
Hui Lu ◽  
Wei Wang ◽  
Aya Ito-Ishida ◽  
Zhenyu Wu ◽  
...  
Keyword(s):  
Social Skills ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Therapeutic Option ◽  
Neurodevelopmental Disorder ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Extended Lifespan ◽  
Inhibitory Signaling

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

scholarly journals Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Alessio Cortelazzo ◽  
Claudio De Felice ◽  
Bianca De Filippis ◽  
Laura Ricceri ◽  
Giovanni Laviola ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Binding Protein ◽  
Neurodevelopmental Disorder ◽  
Unknown Origin ◽  
Apolipoprotein A1 ◽  
Inflammatory Status ◽  
Truncating Mutation ◽  
Alpha 1 Antitrypsin ◽  
First Time

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model.

scholarly journals Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome

2018 ◽  
Vol 115 (23) ◽  
pp. E5363-E5372 ◽  
Author(s):  
Sivan Osenberg ◽  
Ariel Karten ◽  
Jialin Sun ◽  
Jin Li ◽  
Shaun Charkowick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Neuronal Activity ◽  
Intron Retention ◽  
Neurodevelopmental Disorder ◽  
Fine Tuning ◽  
Global Pattern ◽  
Activity Dependent

Rett syndrome (RTT) is a severe neurodevelopmental disorder that affects about 1 in 10,000 female live births. The underlying cause of RTT is mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2); however, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle. Here we reveal an aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity in a mouse model for RTT. Notably, the specific splicing modalities of intron retention and exon skipping displayed a significant bias toward increased retained introns and skipped exons, respectively, in the RTT brain compared with the WT brain. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal activity in RTT mice. Our findings advance the concept that normal MeCP2 functioning is required for fine-tuning the robust and immediate changes in gene transcription and for proper regulation of alternative splicing induced in response to neuronal stimulation.

MeCP2 and Rett syndrome: reversibility and potential avenues for therapy

2011 ◽  
Vol 439 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Kamal K.E. Gadalla ◽  
Mark E.S. Bailey ◽  
Stuart R. Cobb
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Neuronal Morphology ◽  
Environmental Interventions ◽  
Linked Gene ◽  
Synaptic Physiology ◽  
Expression Product ◽  
Mature Neurons ◽  
Neurological Features ◽  
Phenotypic Rescue

Mutations in the X-linked gene MECP2 (methyl CpG-binding protein 2) are the primary cause of the neurodevelopmental disorder RTT (Rett syndrome), and are also implicated in other neurological conditions. The expression product of this gene, MeCP2, is a widely expressed nuclear protein, especially abundant in mature neurons of the CNS (central nervous system). The major recognized consequences of MECP2 mutation occur in the CNS, but there is growing awareness of peripheral effects contributing to the full RTT phenotype. MeCP2 is classically considered to act as a DNA methylation-dependent transcriptional repressor, but may have additional roles in regulating gene expression and chromatin structure. Knocking out Mecp2 function in mice recapitulates many of the overt neurological features seen in RTT patients, and the characteristic postnatally delayed onset of symptoms is accompanied by aberrant neuronal morphology and deficits in synaptic physiology. Evidence that reactivation of endogenous Mecp2 in mutant mice, even at adult stages, can reverse aspects of RTT-like pathology and result in apparently functionally mature neurons has provided renewed hope for patients, but has also provoked discussion about traditional boundaries between neurodevelopmental disorders and those involving dysfunction at later stages. In the present paper we review the neurobiology of MeCP2 and consider the various genetic (including gene therapy), pharmacological and environmental interventions that have been, and could be, developed to attempt phenotypic rescue in RTT. Such approaches are already providing valuable insights into the potential tractability of RTT and related conditions, and are useful pointers for the development of future therapeutic strategies.

scholarly journals Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

2020 ◽  
Author(s):  
Aya Osman ◽  
Nicholas L. Mervosh ◽  
Ana N. Strat ◽  
Katherine R. Meckel ◽  
Tanner J. Euston ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Mouse Model ◽  
Translational Research ◽  
Gut Microbiome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Research Strategies ◽  
Stage Of Development

AbstractAutism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3KO mice. Additionally, we found that Shank3KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

scholarly journals Senescence Phenomena and Metabolic Alteration in Mesenchymal Stromal Cells from a Mouse Model of Rett Syndrome

2019 ◽  
Vol 20 (10) ◽  
pp. 2508 ◽  
Author(s):  
Tiziana Squillaro ◽  
Nicola Alessio ◽  
Stefania Capasso ◽  
Giovanni Di Bernardo ◽  
Mariarosa Melone ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mouse Model ◽  
Cell Fate ◽  
Rett Syndrome ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Biology ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
The Government

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT.

scholarly journals Defects in brainstem neurons associated with breathing and motor function in the Mecp2R168X/Y mouse model of Rett syndrome

2016 ◽  
Vol 311 (6) ◽  
pp. C895-C909 ◽  
Author(s):  
Christopher M. Johnson ◽  
Weiwei Zhong ◽  
Ningren Cui ◽  
Yang Wu ◽  
Hao Xing ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Motor Function ◽  
Neurodevelopmental Disorder ◽  
Motor Dysfunction ◽  
Membrane Properties ◽  
Wild Type ◽  
Lower Body Weight ◽  
Associated Functions ◽  
Intrinsic Membrane Properties

Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mostly by disruption of the MECP2 gene. Among several RTT-like mouse models, one of them is a strain of mice that carries an R168X point mutation in Mecp2 and resembles one of the most common RTT-causing mutations in humans. Although several behavioral defects have previously been found in the Mecp2R168X/Y mice, alterations in nerve cells remain unknown. Here we compare several behavioral and cellular outcomes between this Mecp2R168X/Y model and a widely used Mecp2Bird/Y mouse model. With lower body weight and shorter lifespan than their wild-type littermates, the Mecp2R168X/Y mice showed impairments of breathing and motor function. Thus we studied brainstem CO2-chemosensitive neurons and propriosensory cells that are associated with these two functions, respectively. Neurons in the locus coeruleus (LC) of both mutant strains showed defects in their intrinsic membrane properties, including changes in action potential morphology and excessive firing activity. Neurons in the mesencephalic trigeminal nucleus (Me5) of both strains displayed a higher firing response to depolarization than their wild-type littermates, likely attributable to a lower firing threshold. Because the increased excitability in LC and Me5 neurons tends to impact the excitation-inhibition balances in brainstem neuronal networks as well as their associated functions, it is likely that the defects in the intrinsic membrane properties of these brainstem neurons contribute to the breathing abnormalities and motor dysfunction. Furthermore, our results showing comparable phenotypical outcomes of Mecp2R168X/Y mice with Mecp2Bird/Y mice suggest that both strains are valid animal models for RTT research.

scholarly journals Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dorothy P Schafer ◽  
Christopher T Heller ◽  
Georgia Gunner ◽  
Molly Heller ◽  
Christopher Gordon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Neural Circuits ◽  
Neurodevelopmental Disorder ◽  
Cell Types ◽  
Null Mouse ◽  
Causative Role ◽  
Specific Loss ◽  
Synapse Loss ◽  
Circuit Defects

Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder<xref ref-type="bibr" rid="bib19"/><xref ref-type="bibr" rid="bib15"/><xref ref-type="bibr" rid="bib37"/><xref ref-type="bibr" rid="bib47"/>. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role<xref ref-type="bibr" rid="bib67"/>. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.

scholarly journals Tsix–Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function

2018 ◽  
Vol 115 (32) ◽  
pp. 8185-8190 ◽  
Author(s):  
Lieselot L. G. Carrette ◽  
Roy Blum ◽  
Weiyuan Ma ◽  
Raymond J. Kelleher ◽  
Jeannie T. Lee
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Female Mouse ◽  
Neurodevelopmental Disorder ◽  
Specific Treatment ◽  
Therapeutic Benefit ◽  
Repetitive Behaviors ◽  
Allelic Series ◽  
Neuromotor Function ◽  
Excessive Grooming

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a mutation in the X-linked methyl-CpG-binding protein 2 (MECP2). There is currently no disease-specific treatment, but MECP2 restoration through reactivation of the inactive X (Xi) has been of considerable interest. Progress toward an Xi-reactivation therapy has been hampered by a lack of suitable female mouse models. Because of cellular mosaicism due to random X-chromosome inactivation (XCI), Mecp2+/− heterozygous females develop only mild RTT. Here, we create an improved female mouse model by introducing a mutation in Tsix, the antisense regulator of XCI allelic choice. Tsix–Mecp2 mice show reduced MECP2 mosaicism and closely phenocopy the severely affected Mecp2-null males. Tsix–Mecp2 females demonstrate shortened lifespan, motor weakness, tremors, and gait disturbance. Intriguingly, they also exhibit repetitive behaviors, as is often seen in human RTT, including excessive grooming and biting that result in self-injury. With a Tsix allelic series, we vary MECP2 levels in brain and demonstrate a direct, but nonlinear correlation between MECP2 levels and phenotypic improvement. As little as 5–10% MECP2 restoration improves neuromotor function and extends lifespan five- to eightfold. Our study thus guides future pharmacological strategies and suggests that partial MECP2 restoration could have disproportionate therapeutic benefit.

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