Behavioral and transcriptomic analyses of mecp2 function in zebrafish
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ABSTRACT:
PROVIDER: PRJNA1059618 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27393016_1.fastq.gz | Fastqsanger.gz | |||
| SRR27393016_2.fastq.gz | Fastqsanger.gz | |||
| SRR27393017_1.fastq.gz | Fastqsanger.gz | |||
| SRR27393017_2.fastq.gz | Fastqsanger.gz | |||
| SRR27393018_1.fastq.gz | Fastqsanger.gz |
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Project description:Rett Syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5-7 days post-fertilization (dpf). We show that zebrafish mecp2 function is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2’s function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.
2024-01-01 | GSE252307 | GEO
Project description:Investigation of whole genome gene expression level changes in mecp2 morphant zebrafish embryos as compared to wild-type strain.
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Project description:In this work we investigated how the brain proteome of the larval zebrafish is modified by behavioral adaptation to the environmental challenge of a water vortex. We monitored the behavior of larvae and observed that they behaviorally adapted to the presence of a water vortex. We obtained the larval zebrafish brain proteome by extracting brains from zebrafish larvae and analyzing them using and LFQ-based LC-MS/MS-approach. In total we identified 5929 proteins in the larval brain. Within this proteome, we identified 57 proteins that were significantly regulated following experience of the water vortex: 41 proteins were up regulated and 16 were down regulated. Of these, 29 proteins are known to have neuronal functions, 17 proteins are known to have other cellular functions, and 11 proteins are still uncharacterized.
2019-05-24 | PXD011981 | Pride
Project description:We wanted to analyze the differences in acetyl-H4 content related to inter-individual behavioral variability. We retrieved three groups of samples: The first one was composed by 4 different clusters of zebrafish composed each one by 5 zebrafish larvae. Within each cluster, the behavioral differences across the larvae were minimal, while between the clusters, there were high differences in the behavior. The second one was composed by 4 different clusters of sodium butyrate (NaBu)-treated zebrafish composed each one by 5 larvae. The selection choice was the same as in the first group, but due to their behavioral effect of NaBu, the differences between the clusters were significantly reduced compared to control. The third one was composed by 3 different clusters of 5 zebrafish each randomly selected from the behavioral space. This group is a control of variability not associated to behavior.
2017-09-01 | E-MTAB-5993 | biostudies-arrayexpress
Project description:The goal of this study was to characterize a novel Mecp2 allele in the laboratory rat, a distinct rodent species from the laboratory mouse with unique features. The allele was created by zinc finger-nuclease (ZFN) targeting (SAGE/Horizon) of the X-linked gene, Methyl-CpG-Binding Protein 2 (Mecp2), resulting in normal Mecp2 RNA abundance, but absent protein in male rats as expected due to the presence of only one copy of mutant Mecp2, and an approximate 50% reduction in female rats as expected from animals that harbor one wild-type copy and one mutant copy of Mecp2. Behavioral characterization of female rats with the Mecp2 ZFN allele and wild-type littermates was conducted, and Mecp2 ZFN/+ female rats showed behavioral phenotypes that were consistent with disease-like features present during the early stages of disease onset in the neurological disorder Rett syndrome. The goal of conducting RNAseq studies was to compare existing gene expression alterations in the Mecp2 rat with one of the most widely studied Mecp2 mouse model. Hypothalami were obtained from males with complete loss of MeCP2 (ZFN/y) and wild-type littermate male rats for RNA-seq studies. Common and unique gene expression alterations among the Mecp2 rodents that were then tested in human Rett and control postmortem brain revealed the benefit of combining findings from both models, suggesting the predictive validity of this approach for future studies for the identification of potential preclinical outcome measures. QPCR validation in an independent set of rats was conducted with a subset of genes from the Mecp2 ZFN rat RNA-seq data as an additional control measure. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures. Transcriptional profiles of hypothalamic samples obtained from male rats haboring a novel zinc-finger nuclease Mecp2 loss-of-function allele and corresponding wild-type littermate rats were generated using RNA-seq
2016-08-09 | E-GEOD-83323 | biostudies-arrayexpress
Project description:RNA sequencing was performed on RNA isolated from groups of 6 hpf wild type and mecp2-null embryos (n=3 biological replicates per condition with 30 embryos pooled per replicate). DESeq2 analysis was performed using https://usegalaxy.org/ Whole embryo mRNA profile of 30 pooled mecp2-null or wild type 6 hpf zebrafish embryos, in triplicate, using the Illumina HiSeq4000 platform
2016-09-01 | E-GEOD-80348 | biostudies-arrayexpress
Project description:Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett Syndrome. As a chromatin associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. While neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here we report the identification of several novel MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors. E 15.5 Mecp2 -/y cortical neurons were infected with lentivirus expressing wild-type and S80A mutant MeCP2 at similar protein expression level. 2 biological independent samples and dye swap were used for this set (GSM367413) and replicate 2 set (GSM367414).
2009-02-10 | E-GEOD-14715 | biostudies-arrayexpress
Project description:Lurasidone, a second-generation antipsychotic, is widely used for treating schizophrenia and bipolar disorder due to its favorable metabolic profile. However, its potential developmental neurotoxicity remains poorly understood. This study investigated the effects of lurasidone on zebrafish embryos, combining morphological, behavioral, transcriptomic, and neurotransmitter analyses. Zebrafish embryos were exposed to lurasidone at 0, 0.4, 4, and 8 mg/L concentrations from 5 to 120 hours post-fertilization (hpf). Results revealed dose-dependent developmental toxicity, including reduced survival and hatching rates, shorter body length, and increased pericardial and yolk sac edema. Behavioral assessments showed significant impairments in locomotion and touch response, particularly at higher concentrations. Transcriptomic analysis identified 1,907 differentially expressed genes, with upregulation of circadian regulation pathways and downregulation of cell cycle and oxidative phosphorylation pathways. Neurotransmitter profiling indicated significant reductions in glutamate, dopamine, and GABA levels, suggesting disruptions in excitatory/inhibitory balance. These findings highlight lurasidone's potential neurodevelopmental risks, particularly during critical developmental periods. The study underscores the importance of further research to assess the safety of lurasidone in vulnerable populations, such as pregnant women and young patients.
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Project description:Neurodevelopmental disorders (NDDs) are genetically heterogeneous, yet often share certain features such as intellectual disability or motor incoordination. MeCP2 dysfunction is associated with MECP2 duplication syndrome and Rett syndrome (RTT), the phenotypes of which overlap with other NDDs, yet the precise molecular pathogenesis remains unclear. Using proximity-dependent biotinylation (BioID), we identified a novel TCF20 complex that interacts with MeCP2 through its subunit PHF14. TCF20 regulates the expression of key neuronal genes, many of which are co-regulated by MeCP2. Reducing Tcf20 partially rescued the behavioral deficits caused by MECP2 overexpression, underscoring a functional relationship between MeCP2 and TCF20 in NDD pathogenesis. We identified a patient with a missense mutation in PHF14 that abolishes the MeCP2-PHF14-TCF20 interaction who exhibits neurological features seen in RTT. These data demonstrate the critical role of MeCP2-TCF20 complex interaction for brain function.
2022-01-24 | GSE179229 | GEO
Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome, an X-linked neurodevelopmental disorder. We previously found that Mecp2-null microglia are functionally impaired, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. In this study we show that Mecp2 is expressed in macrophage and monocyte populations throughout the body, and is indispensable for their transcriptional regulation in multiple contexts. We demonstrate that Mecp2-null mice progressively lose or are chronically deficient in several macrophage populations and resident monocytes. Postnatal re-expression of Mecp2 driven by a tamoxifen-inducible CX3CR1 promoter significantly increased the lifespan of otherwise Mecp2-null mice, suggesting that epigenetic regulation of macrophage function by Mecp2 significantly contributes to pathology. RNA-Seq of acutely isolated microglia and peritoneal macrophages (to our knowledge, the first cell-specific RNA-Seq analysis comparing Mecp2-null and wild type cells of any kind) revealed significantly increased transcription of glucocorticoid- and hypoxia-signaling genes in Mecp2-null cells compared to that in their wild-type counterparts, suggesting that Mecp2 functions as a repressor of these pathways. Furthermore, in-vitro and in vivo validation studies demonstrated that the absence of Mecp2 is associated with cell-intrinsic dysfunction of signaling underlying inflammatory activation, suggesting that Mecp2 is important for regulation of specific macrophage gene-expression programs in response to stimuli and stressors. Our findings demonstrate a fundamental role for Mecp2 in the regulation of macrophage functions, which may provide a link to pathologies in Rett syndrome across multiple organs. Mecp2-null microglia and resident peritoneal macrophages from 10-12 week old mice were acutely isolated via AutoMACS, total RNA collected, and analyzed via RNA-Seq to compare for transcriptional differences in microglia and macrophages in the absence of Mecp2.
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