RNA-seq transcriptional profiling in sciatic nerves from wildtype and Pmp22 transgenic rats during perinatal development
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE115930 | GEO | 2018/06/19
REPOSITORIES: GEO
Similar Datasets
Project description:Peripheral myelin protein 22 (PMP22) is a tetraspan integral membrane protein for which mistrafficking-causing mutations are linked to the inherited peripheral neuropathy, Charcot-Marie-Tooth disease (CMTD). Wild type (WT) PMP22 is an inefficient folder with ~20% of the protein trafficking to the plasma membrane. We discovered that N-linked glycosylation significantly limits forward trafficking of WT and disease variants of PMP22. N-glycosylation of WT PMP22 was found to occur primarily post-translationally. Glycosylation inhibition dramatically increased PMP22 trafficking efficiency. Quantitative proteomics identified novel PMP22 interacting proteins that may impact trafficking. Our results suggest that critical quality control decisions for unstable L16P PMP22 occur at earlier stages in the trafficking pathway than for the WT protein. Knock-out cell lines of likely PMP22 interactors led to the discovery that calnexin limits trafficking of stable PMP22 variants, UGGT1 promotes trafficking and RER1 limits trafficking of all PMP22 variants. This work establishes N-glycosylation as a key determinant of PMP22 retention in the ER, ultimately limiting forward surface-trafficking.
2021-04-27 | PXD023091 | Pride
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
Project description:Here, human induced pluripotent stem cells (control-hiPSCs, CMT1A-hiPSCs, and PMP22-hiPSCs) were induced to differentiate to Schwann cells (control-SCs, CMT1A-SCs, and PMP22-SCs) through neural crest stage (control-NCSCs, CMT1A-NCSCs, and PMP22-NCSCs). We sequenced mRNA samples from Schwann cell differentiation of human pluripotent stem cells at 3 different stage to generate the gene expression profiles of these cells.
2018-02-14 | GSE97851 | GEO
Project description:RNA-seq transcriptional profiling in sciatic nerves from wildtype and Pmp22 transgenic rats during perinatal development
| PRJNA476542 | ENA
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:Cancer stem cells (CSCs) possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the Explorer Antibody Microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received 6 cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer.
2017-02-10 | GSE94714 | 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 | 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 | 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.
2019-05-01 | GSE122775 | 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