Cell-type-specific profiling of defects in translation and neurogenesis in a human iPSC model of fragile X syndrome
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ABSTRACT:
PROVIDER: PRJNA610179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11235123_1.fastq.gz | Fastqsanger.gz | |||
| SRR11235123_2.fastq.gz | Fastqsanger.gz | |||
| SRR11235124_1.fastq.gz | Fastqsanger.gz | |||
| SRR11235124_2.fastq.gz | Fastqsanger.gz | |||
| SRR11235125_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to loss of the RNA-binding protein, FMRP. In addition to its well-established role of regulating protein synthesis, emerging evidence suggests that FMRP acts to coordinate proliferation and differentiation during early neural development. However, whether translational control by FMRP drives critical cellular events of fate specification and developmental transitions in the developing human brain remains unknown. Here, we have designed a high-throughput, in vitro assay that allows for the simultaneous quantification of protein synthesis and proliferation within defined neural subpopulations. Using iPSC-derived neural progenitor cells and organoids to model human cortical neurogenesis in FXS, we show that abnormal protein synthesis during early development alters cellular decisions to favor proliferative over neurogenic cell fates.
2021-04-12 | GSE146339 | GEO
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
Project description:FXS (Fragile X Syndrome), a leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by an expansion of a CGG repeat in the 5′-UTR of the FMR1 (Fragile X Mental Retardation-1) gene. While current studies of FXS have focused on the effects of Fragile X Mental Retardation Protein (FMRP) loss in excitatory neurons, evidence suggests that GABAergic inhibitory networks are also affected in FXS. In this study, we developed a method to reproducibly derive GABAergic inhibitory neurons from multiple FXS and control human pluripotent stem cell lines (PSCs). We found that compared to control, functional assays with microelectrode arrays and immunocytochemistry suggested a developmental delay in the maturing FXS inhibitory network that involves the GABA function switch. The GABA function switch converts the GABAA channel’s role from depolarization to hyperpolarization and has profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14,400 single-cell transcriptomes from FXS and control PSC-derived GABAergic neuron cultures at early and late stages of neurogenesis. Genes related to neuroblast proliferation were upregulated in FXS cells, while neuron-specific differentially expressed genes (DEGs) associated with action potential regulation, synaptic processes, and mitochondria function were downregulated in FXS cells. In addition, autism-associated genes were overrepresented in the DEGs. Our analysis of inhibitory neuron development suggests that loss of FMRP is associated with delays in the GABAergic neurogenesis and maturation. This observation suggests a novel direction for understanding the underlying disease mechanisms and may help to guide development of therapeutic interventions.
2022-06-29 | GSE198138 | GEO
Project description:Fragile X syndrome (FXS) is one of the most prevalent inherited intellectual disabilities. The patients carry the expansion of over 200 CGG repeats located at the 5′ untranslated region of fragile X mental retardation 1 (FMR1). As a result, the FMR1 promoter becomes hypermethylated leading to decreased or absent expression of its encoded RNA-binding protein fragile X mental retardation protein (FMRP). We previously generated human induced pluripotent stem (iPS) cells from fibroblasts of a FXS patient (FXS-iPSC) with expanded CGG-repeats at the FMR1 promoter. In the present work, we explored the transcriptional misregulation during the embryonic neurogenesis by in-vitro differentiation of FXS-iPSC into neurons through the intermediate stages. At each differentiation stage, we collected RNA and performed RNA-seq. After an integrated analysis, we found up-regulation of many genes encoding TFs for neuronal differentiation (WNT1, BMP4, POU3F4, TFAP2C, and PAX3), down-regulation of potassium channels (KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9, and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. Furthermore, we found the cholesterol synthesis genes (e.g., SQLE, LSS, and FASN) are up-regulated during the in-vitro neuronal differentiation of FXS-iPSC, which may contribute to the obesity phenotype of FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, and also discovered many potential candidate genes for the cure of FXS symptoms such as neuronal abnormalities and obesity.
2016-03-04 | GSE76490 | GEO
Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.
| S-EPMC3412379 | biostudies-literature
Project description:Human iPSC-derived organoids modeling the etiology of pregestational diabetes induced congenital heart defects
2023-08-07 | GSE201343 | GEO
Project description:Translation-dependent quality control pathways govern protein synthesis and proteostasis by degrading potentially toxic peptide products derived from aberrant mRNAs. However, little is known about the in vivo defects that arise in the absence of these pathways and how translation is altered in the absence of these pathways. Here, we demonstrate that the ribosome rescue factors Pelo/Hbs1l are both critical for embryonic and neuronal development but dispensable for neuronal survival in the adult brain. Loss of Pelo/Hbs1l in cerebellar progenitors impaired differentiation of these cells. Our analysis of Pelo/Hbs1l deficient fibroblasts revealed translational reprogramming of multiple pathways including mTORC1 signaling likely to restore cellular homeostasis. Interestingly, similar affects on the translatome, signaling pathways and neurogenesis were observed when we conditionally deleted Upf2 to inhibit NMD. These data reveal that translation-dependent quality control pathways, which set out to mitigate errors in translation and to clear defective peptide products and aberrant mRNAs can trigger similar cellular responses and neurodevelopmental abnormalities.
2021-03-15 | GSE162556 | GEO
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