Modeling the pathogenesis of Charcot-Marie-Tooth disease type 1A using patient-specific iPSCs
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97851 | GEO | 2018/02/14
REPOSITORIES: GEO
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Project description:We obtained skin fibroblasts from CMT1A and control patients, and generated hiPSCs which were subsequently differentiated into cd49d+ human Schwann cells. We utilized microarray technology to explore the gene expression profiles of cd49d+ Schwann cells CMT1A hiPSCs, control hiPSCs, and control human embryonic stem cells in order to identify potentially disregulated pathways contributing to CMT1A pathogenesis. Patient-specific human induced pluripotent stem cells (hiPSCs) hold great promise for disease modeling of genetic disorders. Often the findings from hiPSC-based studies are validated with genetically-corrected hiPSCs generated by precise genome editing technologies, however, alternatives that have not yet been employed are validation with embryonic stem cells harboring the same disease mutation or utilizing another reprogramming approach from somatic cells of same patients. Here we report that disease-relevant phenotypes found in Charcot-Marie-Tooth 1A (CMT1A)-hiPSC-derived Schwann cells were further confirmed by two additional congruent CMT1A models as an alternative to gene correction. We have devised a defined and relatively fast protocol for the direct derivation and prospective isolation of Schwann cells from hiPSCs, leading us to uncover a phenotype of dysregulated immune signaling in CMT1A-hiPSCs-Schwann cells. Our study illustrates the promise of applying hiPSC technology to one of the most common hereditary neuropathies for gaining new insights into human disease pathogenesis and treatment, and these results demonstrate the feasibility of verifying disease phenotypes by utilizing the malleability of cellular fates.
2019-05-22 | GSE69988 | GEO
Project description:Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.
2019-05-01 | GSE122776 | GEO
Project description:Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.
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Project description:Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.
2019-05-01 | GSE122773 | GEO
Project description:Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.
2019-05-01 | GSE122774 | GEO
Project description:The goal of this study was to identify deregulated genes in Schwann cells of Pmp22 transgenic rats in comparison to wildtype rats. Three timepoints in the course of peripheral nerve myelination were chosen (embryonic day [E] 21, perinatal day [P]6 and P18) in order to reveal mechanistic insight into early pathological processes of Charcot-Marie-Tooth disease 1A (CMT1A).
2018-06-19 | GSE115930 | GEO
Project description:Here, control human pluripotent stem cells (hiPSCs) and SOX10 knockout (SOX10 KO) hiPSCs were induced to differentiate to neural crest stem cells (NCSCs). We sequenced mRNA samples of differentiated cells at day 7 during NCSC differentiation to generate the gene expression profiles of these cells.
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Project description:Here, Down syndrome-specific hiPSCs (DS1-hiPSCs and DS2-hiPSCs) were induced to differentiate to neural crest stem cells (NCSCs). We sequenced mRNA samples of DS1-NCSCs and DS2-NCSCs to generate the gene expression profiles of these cells.
2022-12-02 | GSE190305 | GEO
Project description:Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves protein misfolding and retention in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1/XBP1 pathways. Previous studies have reported that targeting PERK pathway can mitigate the neuropathy in CMT1B mice. To unravel the role of the XBP1 pathway in normal myelination and in CMT1B, we generated mouse models of in which XBP1 is deleted specifically in Schwann cells. We observed that whereas XBP1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury, the absence of XBP1 dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1 exerts its adaptive function in large part via the induction of genes involved in misfolded protein degradation. Accordingly, the exacerbation of the neuropathy was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling, suggesting that the activation of XBP1 plays a critical role in limiting mutant proteins toxicity, which cannot be compensated by other stress responses. Schwann cell specific overexpression of spliced XBP1 partially re-established Schwann cell proteostasis and attenuated CMT1B severity in vivo in both the S63del and R98C mouse models. In addition, the pharmacologic selective activation of XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants.
2024-01-15 | GSE252089 | GEO
Project description:Charcot-Marie-Tooth 1A is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), which produces muscle weakness and loss of sensation in the hands and feet. A recent case-only genome wide association study by the Inherited Neuropathy Consortium identified a strong association between variants in signal induced proliferation associated 1 like 2 (SIPA1L2) and strength of foot dorsiflexion. To validate SIPA1L2 as a candidate modifier, and to assess its potential as a therapeutic target, we engineered mice with a deletion in SIPA1L2 and crossed them to the C3-PMP22 mouse model of CMT1A. We performed neuromuscular phenotyping and identified an interaction between Sipa1l2 deletion and muscular endurance decrements assayed by wire-hang duration in C3-PMP22 mice, as well as several interactions in femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggested an involvement of Sipa1l2 in cholesterol biosynthesis, which was also implicated in C3-PMP22 mice. Though several interactions between Sipa1l2 deletion and CMT1A-associated phenotypes were identified, validating a genetic interaction, the overall effect on neuropathy was small.
2023-12-12 | GSE249764 | GEO