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Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome Model

ABSTRACT: Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome Model

PROVIDER: PRJNA613291 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11348439_1.fastq.gz	Fastqsanger.gz
	SRR11348439_2.fastq.gz	Fastqsanger.gz
	SRR11348440_1.fastq.gz	Fastqsanger.gz
	SRR11348440_2.fastq.gz	Fastqsanger.gz
	SRR11348441_1.fastq.gz	Fastqsanger.gz

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Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome Model

Project description:Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. We performed single cell RNA-seq from the cortex of both Fmr1-knock out (Fmr1-KO) and wild type (WT) FVB animals at postnatal day 5. After stringent filtering, we obtained 18,393 cells for which we detected an average of 1,778 genes and 3,988 transcripts. We identified a total of 18 distinct populations, these include vascular cells (endothelial cells and pericytes), fibroblasts, ependymal cells, different neuron subtypes and glial cells. Our findings present new insights into the cell type specific consequences of FXS. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.

2020-03-19 | GSE147191 | GEO

Single cell transcriptomics reveals dysregulated cellular and molecular networks in a fragile X syndrome model.

Project description:Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular basis is still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative, therefore we applied single cell RNA sequencing to profile an FMRP deficient mouse model with higher resolution. We found that the absence of FMRP results in highly cell type specific gene expression changes that are strongest among specific neuronal types, where FMRP-bound mRNAs were prominently downregulated. Metabolic pathways including translation and respiration are significantly upregulated across most cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways, suggest an excitatory-inhibitory imbalance in the Fmr1-knock out cortex that is exacerbated by astrocytes. Our data demonstrate that FMRP loss affects abundance of key cellular communication genes that potentially affect neuronal synapses and provide a resource for interrogating the biological basis of this disorder.

| S-EPMC9212148 | biostudies-literature

Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells

Project description:Fragile X syndrome (FXS) is caused by the absence of the fragile X mental retardation protein (FMRP). We have previously generated FXS-induced pluripotent stem cells (iPSCs) from patients' fibroblasts. In this study, we aimed at unraveling the molecular phenotype of the disease. Our data revealed aberrant regulation of neural differentiation and axon guidance genes in FXS-derived neurons, which are regulated by the RE-1 silencing transcription factor (REST). Moreover, we found REST to be elevated in FXS-derived neurons. As FMRP is involved in the microRNA (miRNA) pathway we employed microRNA-array analyses and uncovered several miRNAs dysregulated in FXS-derived neurons. We found hsa-mir-382 to be down-regulated in FXS-derived neurons, and introduction of mimic-mir-382 into these neurons was sufficient to repress REST and up-regulate its axon guidance target genes. Our data link, FMRP and REST, through the miRNA pathway, and show a new aspect in the development of FXS. Affimetrix miRNA array of two WT and two fragile X syndrome derived neurons

2014-10-28 | E-GEOD-62721 | biostudies-arrayexpress

p70 S6 Kinase 1-dependent alterations in cortical mRNA translation in fragile X syndrome mice

Project description:Fragile X syndrome (FXS) is caused by loss of the fragile X mental retardation protein (FMRP). The mechanism by which FMRP regulates messenger RNA (mRNA) translation remains disputed. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in cortices of FXS mice, which was correlated with an increased rate of ribosome translocation that was normalized by inhibition of p70 S6 Kinase 1 (S6K1). We also show that alterations in translation efficiencies across mRNAs in FXS mouse cortices exhibit a positive to negative gradation with coding sequence length, which is prevented by the genetic reduction of S6K1. Our findings reveal the identity of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

2020-10-31 | GSE143659 | GEO

Unbalanced protein expression contributes to pathology in Fragile X Syndrome

Project description:Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y). Our results identify a robust translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1-/y neurons. In addition, proteomics analyses identify increased degradation of multiple proteins at hippocampal synapses, many of which are underexpressed at steady-state.

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Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells

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