Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE260669 | GEO | 2024/03/06
REPOSITORIES: GEO
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Project description:Extensive transcriptomic changes associated with paclitaxel-induced peripheral neuropathy in mice: Differential effects in dorsal root ganglia and the sciatic nerve Background: Paclitaxel (Ptx)-induced peripheral neuropathy (PIPN), a common side effect of this anti-cancer drug, causes chronic pain reflecting the molecular changes in the dorsal root ganglion (DRG) of the sciatic nerve (SN). While the subcellular localization and spatio-temporal control of mRNA translation are critical to nerve function, little is known about the transcriptional landscapes of DRG and SN in PIPN. Aim: Transcriptome-wide assessment of Ptx-induced changes in gene expression and mRNA distribution in DRG or SN. Methods: Gene expression microarray analysis of the subcellular transcriptomes of DRG and SN in normal and PIPN mice with Transcriptome Analysis Console followed by analysis with 11 pathway databases. Validation of selected results in cultured cells and animal tissues. Results: In normal mice, transcripts were differentially distributed in DRG and SN. In PIPN, both the gene expression profile and the distribution of the transcripts between DRG and SN were changed compared to normal controls. Functional analysis of gene clusters confirmed changes in pathways known to be affected by Ptx including including cytoskeleton remodeling, cell cycle regulation, immune response and neuronal transmission, as well as less studied pathways such as fatty acid metabolism, Rho GTPases in Wnt signaling, G-protein signal transduction, mRNA splicing and editing. Although the expression and function of cytoskeleton genes is known to be disturbed by Ptx, we found actins, actinins and non-muscle myosins (actomyosin contractility cluster) to be overexpressed by Ptx and accumulated specifically in the SN. For instance, in PIPN, the normalized ratio of SN/DRG mRNA levels for Myh7, Myh2, Actn2, Acta2 and Actb was 32.4, 24.5, 21.9, 3.6 and 3.3 respectively. We also identified transcripts overexpressed and accumulated in PIPN DRGs, with the highest DRG/SN mRNA ratios found for ion channels (ratios in parentheses) SN10a, Kcnd1, Atp1a3, Kcnip3, SN11a, (10.3-21.2); neurotransmitter regulators Syt1, Gabbr2 (14.4, 13.2); fatty acid regulators: Fabp4, Adipoq (22.9, 4.8), some tubulins: Tubb3, Tubb4a, Tubb4b (9.15, 5.5, 2.0) as well as GPCR regulating proteins: Rasgrp1, Gnal, Olfr1098 (16.7, 7.6, 2.0). Furthermore, the Wikipathways integrated with the Transcriptome Analysis Console revealed that GPCRs were the most significantly altered class of genes, predominantly downregulated by Ptx compared to Naive samples in the DRG (320 downregulated, 88 upregulated) and in the SN (469 downregulated, 74 upregulated). In contrast, the comparison of control Naive samples in the DRG versus SN showed minimal changes (21 downregulated, 5 upregulated). These changes were statistically significant with a p-value < 0.001 and a fold change of -2 > FC > 2. Conclusion: Our results show that Ptx not only affects the gene expression but also the subcellular localization of transcripts kept in DRG bodies or over-transported to distal parts of Sciatic Nerve along the longest axon of the body. Cargo trafficking including RNA shuttles among nucleus- cytoplasm-axon terminal of nerves might be one of the most critical processes impaired in PIPN. These results might be used in the future to develop a potential therapeutic strategy focusing on normalization of axon cargo trafficking and PIPN prevention.
2023-12-08 | GSE249643 | GEO
Project description:Website for easy exploration of the data: https://rna-seq-browser.herokuapp.com/# For the first time, we here characterize the transcriptional signature of satellite glial cells (SGCs) in a nerve injury-paradigm by isolating SGCs from mouse dorsal root ganglia (DRGs) after peripheral nerve injury followed by next generation RNA sequencing (RNA-seq). We found that SGCs regulate their gene expression differently at 3 days and 14 days after peripheral nerve injury suggesting that they change their function over time. At both time points, we found downregulation of several genes linked to cholesterol. After 14 days we further detect regulation of genes linked to the immune system (MHC protein complex and leukocyte migration). The SGC RNA-seq data is accompanied by RNA-seq of purified nociceptors from injured (partial sciatic nerve ligation) or sham (ipsi after sham operation or contra after partial sciatic nerve ligation) L3-L5 DRGs.
2020-01-22 | GSE120284 | GEO
Project description:Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis.
| PRJNA1082668 | ENA
Project description:Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.
2022-06-15 | GSE206043 | GEO
Project description:Six different mouse pain models were studied: (1) tumour-injection model for bone cancer pain; (2) partial sciatic nerve ligation (PSL) for neuropathic pain; (3) mechanical joint loading for osteoarthritis pain; (4) oxaliplatin-induced painful neuropathy for chemotherapy-induced pain; (5) hyperalgesic priming model for chronic muscle pain; and (6) complete Freund’s adjuvant (CFA)-injection for inflammatory pain. Transcriptomic microarray analyses were performed using RNA isolated from dorsal root ganglia.
2018-06-11 | E-MTAB-6864 | biostudies-arrayexpress
Project description:To elucidate the molecular mechanisms underlying the neuroprotective role of S1P2, we conduct RNASeq on dorsal root ganglions (DRGs) collected from a cisplatin-induced peripheral neuropathy (CIPN) rat model.
2024-07-01 | GSE235877 | GEO
Project description:Chronic, often intractable pain is caused by neuropathic conditions such as peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations that don’t depend on peripheral axotomy and associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes and long noncoding RNAs. Many transcriptomic changes after SCI were also found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between any rat neuropathic pain model and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural and tissue injury. Although few genes in DRG cells show similar changes in gene expression across all these painful conditions, the few widely shared transcriptional alterations promise novel insights into fundamental mechanisms within DRGs that can drive neuropathic pain.
2022-10-20 | GSE202111 | GEO
Project description:Hedgehog (Hh) signaling is critical for organogenesis, tissue homeostasis, and stem cell maintenance. Smoothened (SMO), the primary effector of Hh signaling, is expressed ectopically in human breast cancer, as well as in other cancers. Constitutive activation of SMO in mouse mammary glands leads to paracrine stimulation of proliferation, as well as hyperplasia. In canonical signaling, SMO functions via GLI transcription factor activation. However, recent data from Drosophila and mammalian cell lines indicate that SMO can function non-canonically as a G-protein coupled receptor (GPCR) by coupling to heterotrimeric G proteins, particularly those in the pertussis toxin (PTX)-sensitive G-alpha-i (Gai) class. Whether SMO functions as a GPCR in mammalian tissues in vivo is not known. Using genetically modified mouse models, we demonstrate here that SMO-induced stimulation of proliferation is PTX sensitive, and requires Gai2, but not Gai1 or Gai3. Our findings provide evidence for a non-canonical GPCR function of activated SMO in vivo, a finding that may have clinical significance given that most SMO-targeted agents were selected based largely on their ability to block canonical GLI-mediated transcription. Primary mammary epithelial cell RNA was deep-sequenced from mT-mG/SmoM2;MMTV-Cre (EGFP), mT-mG/SmoM2;MMTV-Cre (tdTomato), and mT-mG/SmoM2;+ cells to examine the effects of SmoM2 overexpression in the mammary gland.
2015-09-08 | E-GEOD-70210 | biostudies-arrayexpress
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).
2014-09-29 | E-GEOD-60033 | biostudies-arrayexpress
Project description:Paclitaxel-induced peripheral neuropathy is a significant problem, which afflicts up to 70% of chemotherapy patients. Therapeutic interventions are currently unavailable due to an incomplete understanding of the underlying mechanisms. We previously discovered a major target in the skin, MMP-13, which underlies the development of paclitaxel-induced peripheral neuropathy in zebrafish and rodents. To better understand gene expression changes in sensory neurons and target tissue prior to and during the progression of neuropathy, we performed longitudinal RNA sequencing of mouse skin and dorsal root ganglion (DRG) neurons. Samples were harvested at time points associated with behavioural responses following injection of mice for 7 days either with vehicle or paclitaxel. The responses were categorized into pain onset (day 4 of paclitaxel injection), maxima (d7), beginning of pain resolution (d11) and recovery phase (d23). This dataset will be useful to understand changes in gene regulation in both neurons and skin, which can aid in the discovery of therapeutic interventions.
2021-10-12 | GSE185084 | GEO