Sex differences in nociceptor translatomes contribute to divergent prostaglandin signaling in male and female mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE155676 | GEO | 2020/08/05
REPOSITORIES: GEO
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Project description:Sex differences in nociceptor translatomes contribute to divergent prostaglandin signaling in male and female mice
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Project description:Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification (TRAP) to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. TRAP sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. We identified Gpr88 as upregulated and Metrn as downregulated. We confirmed a functional role for these genes, wherein a GPR88 agonist causes pain only in primed mice and established hyperalgesic priming is reversed by Meteorin. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming.
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Project description:We show differences in translatome of the DRG from ribo tagged mice fed normal chow or western diet.
2022-06-29 | GSE198895 | GEO
Project description:We show differences in translatome of the sensory neurons of the DRG primary neurons treated with LXR agonist GW3965.
2022-06-29 | GSE198898 | GEO
Project description:Unbiased 'omics' techniques, such as next generation RNA-sequencing, can provide entirely novel insights into biological systems. However, cellular heterogeneity presents a significant barrier to analysis and interpretation of these datasets. The neurons of the dorsal root ganglia (DRG) are an important model for studies of neuronal injury, regeneration and pain. The majority of investigators utilize a dissociated preparation of whole ganglia when studying cellular and molecular function. We demonstrate that the standard methods for producing these preparations gives a 10%-neuronal mixture of cells, with the remainder of cells constituting satellite glia and other non-neuronal cell types. Using a novel application of magnetic purification, we consistently obtain over 95% pure, viable neurons from adult tissue, significantly enriched for small diameter nociceptors expressing the voltage gated ion channel Nav1.8. Using genome-wide RNA-sequencing we compare the currently used (10% neuronal) and pure (95% nociceptor) preparations and find 920 genes enriched. This gives an unprecedented insight into the molecular composition of small nociceptive neurons in the DRG, potentially altering the interpretation of previous studies performed at the tissue level, and indicating a number of novel markers of this widely-studied population of cells. We anticipate that the ease of use, affordability and speed of this technique will see it become widely adopted, delivering a greatly improved capacity to study the roles of nociceptors in health and disease. RNA-Seq was performed for 4 biological replicates from three different groups: intact DRG, acutely dissociated DRG and magnetically-purified DRG neurons. Differential expression was analyzed between acutely dissociated and MACS-dissociated samples to define the 'nociceptor transcriptome'.
2014-11-17 | E-GEOD-62424 | biostudies-arrayexpress
Project description:Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and longterm disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period, hours after stroke, have not been elucidated. We used the RiboTag technique to obtain Astrocyte IP and microglia-derived mRNA transcripts in a hyperacute (4 hours) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation. Microglia initiated a rapid response to stroke at 4 hours by adopting an inflammatory profile associated with the recruitment of immune cells. The hyperacute Astrocyte IP profile was marked by stress response genes and transcription factors, such as Fos and Jun, involved in pro-inflammatory pathways such as TNF-α. By 3 days, microglia shift to a proliferative state and Astrocyte IPs strengthen their inflammatory response. The Astrocyte IP pro-inflammatory response at 3 days is partially driven by the upregulation of the transcription factors C/EBPβ, Spi1, and Rel, which comprise 25% of upregulated transcription factor-target interactions. Surprisingly, few sex differences across all groups were observed. Expression and log2 fold data for all sequenced genes are available on a user-friendly website for researchers to examine gene changes and generate hypotheses for stroke targets. Taken together our data comprehensively describe the Astrocyte IP and microglia-specific translatome response in the hyperacute and acute period after stroke and identify pathways critical for initiating neuroinflammation.
2023-02-14 | GSE225110 | GEO
Project description:We evalueted gene expression in dorsal root ganglion (DRG) over-expressing NRG1 typeIII ICD (Intra Cellular Domain). DRG were infected with a lentivirus expressing ICD and compared to not infected DRG or DRG infected with a lentivirus expressing EGFP.
2014-12-14 | E-MTAB-2131 | biostudies-arrayexpress
Project description:Transcriptional control by gonadal hormone nuclear receptors is the foundation for sex-dependent physiological processes, including pain. Our current findings point to sex-dependent translation control as a new mechanism for sexual dimorphisms in pain. We show that hindpaw or spinal administration of exogenous prolactin (PRL) induces thermal and mechanical hyperalgesia in a female-selective fashion. Unexpectedly, PCR and transcriptomic analysis of hindpaw and dorsal root ganglion (DRG) tissues reveal no differences in PRL receptor (Prlr) mRNA between sexes. Variance in overall hindpaw and DRG transcriptomes between females and males were minor. We find that Prlr mRNA and protein is mainly expressed by peptidergic nociceptors as shown by profiling using Prlr reporter mice and electrophysiology, but there are far more peptidergic neurons with functional Prlr in females than in males. In line with this, exogenous PRL increased excitability only in female neurons. Moreover, in male DRG neurons, 6-24 hr estrogen exposure establishes PRL sensitivity in Prlr mRNA+ male neurons that do not show PRL responses under other conditions. PRL-induced behavioral hypersensitivity as well as sensitivity to PRL in female DRG neurons can be ablated by treatment with cap-dependent translation inhibitor 4EGI-1. Spinal cord immunohistochemistry of Prlr reporter mice highlight that Prlr protein is only found in female DRG neurons, but Prlr mRNA localizes to central terminals of male and female sensory neurons. Based on these findings, we propose a novel mechanism for sex-dependent regulation Prlr mRNA translation that renders female DRG neurons uniquely responsive to PRL.
2019-03-01 | GSE121645 | GEO
Project description:Transcriptional control by gonadal hormone nuclear receptors is the foundation for sex-dependent physiological processes, including pain. Our current findings point to sex-dependent translation control as a new mechanism for sexual dimorphisms in pain. We show that hindpaw or spinal administration of exogenous prolactin (PRL) induces thermal and mechanical hyperalgesia in a female-selective fashion. Unexpectedly, PCR and transcriptomic analysis of hindpaw and dorsal root ganglion (DRG) tissues reveal no differences in PRL receptor (Prlr) mRNA between sexes. Variance in overall hindpaw and DRG transcriptomes between females and males were minor. We find that Prlr mRNA and protein is mainly expressed by peptidergic nociceptors as shown by profiling using Prlr reporter mice and electrophysiology, but there are far more peptidergic neurons with functional Prlr in females than in males. In line with this, exogenous PRL increased excitability only in female neurons. Moreover, in male DRG neurons, 6-24 hr estrogen exposure establishes PRL sensitivity in Prlr mRNA+ male neurons that do not show PRL responses under other conditions. PRL-induced behavioral hypersensitivity as well as sensitivity to PRL in female DRG neurons can be ablated by treatment with cap-dependent translation inhibitor 4EGI-1. Spinal cord immunohistochemistry of Prlr reporter mice highlight that Prlr protein is only found in female DRG neurons, but Prlr mRNA localizes to central terminals of male and female sensory neurons. Based on these findings, we propose a novel mechanism for sex-dependent regulation Prlr mRNA translation that renders female DRG neurons uniquely responsive to PRL.
2023-11-17 | GSE161826 | GEO
Project description:Aging is the main risk factor for age-related macular degeneration (AMD), a retinal neurodegenerative syndrome that leads to irreversible blindness, particularly in people over 60 years old. Retinal pigmented epithelium (RPE) atrophy is an AMD hallmark that often precedes photoreceptor loss. Genome-wide chromatin accessibility, DNA methylation, and gene expression studies of AMD and control RPE demonstrate epigenomic/transcriptomic changes occur during AMD onset and progression. However, mechanisms by which molecular alterations of normal aging impair RPE function and contribute to AMD pathogenesis are unclear. Here, we specifically interrogate the RPE translatome with advanced age and across sexes in a novel mouse model. We find differential age- and sex- associated transcript expression with overrepresentation of pathways related to inflammation in the RPE. Concordant with impaired RPE function, the phenotypic changes in the aged translatome suggest that aged RPE becomes immunologically active, in both males and females, with some sex-specific signatures, which supports the need for sex representation for in vivo studies.
2024-05-13 | GSE245595 | GEO