Translation Regulation of the Prolactin Receptor Defines Sexually Dimorphic Pain Responses to Prolactin
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE121645 | GEO | 2019/03/01
REPOSITORIES: GEO
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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:Sensory neurons in the dorsal root ganglia (DRG) convey somatosensory and metabolic cues to the central nervous system and release substances locally from stimulated terminal endings in peripheral organs. Sex-biased variations driven by the sex chromosome complement (XX and XY) have been implicated in the sensory-islet crosstalk. However, the identity of the molecules underlying male-female differences is not known. Here, we aim to characterize the molecular repertoire and the secretome profile of the spinal sensory neurons in sexually immature male and female mice to identify molecules with sex-biased insulin sensing- and/or insulin secretion-modulating activity. We used transcriptomics and proteomics to uncover differentially expressed genes and secreted molecules in DRG sensory neurons derived from 3-week-old male and female C57BL/6J mice. Comparative transcriptome and proteome analyses revealed differential gene expression and protein secretion in DRG neurons in males and females. Interestingly, gene ontology annotation highlighted sex differences in epigenetic regulation, cell cycle, DNA replication and insulin signaling pathways. Secretome analysis uncovered several sex-based variations in conventionally and unconventionally sensory-secreted proteins with potential roles in β-cell function-modulating activity. Collectively, we provide a valuable resource of molecular and secretory targets that can be leveraged for understanding sex differences in DRG sensory neurons. Some of these candidates have translational value as they can inform the development of novel sex-based therapeutic opportunities for individuals with compromised β-cell activity.
2023-09-20 | GSE228189 | GEO
Project description:Prolactin (Prl) is a pleiotropic hormone with multiple functions in several tissues and organs, including the brain. In the hippocampus, Prl has been implicated in several functions, including neuroprotection against excitotoxicity in lactating rats and in Prl-treated ovariectomized animals. However, the molecular mechanisms involved in Prl actions in the hippocampus have not been completely elucidated. The aim of this study was to analyse the hippocampal transcriptome of female Prl-treated ovariectomized rats. Transcriptomic analysis by RNASeq revealed 162 differentially expressed genes throughout 24 h of Prl treatment. Gene Ontology analysis of those genes showed that 37.65% were involved in brain processes that are regulated by the hippocampus, such as learning, memory and behaviour, as well as new processes that we did not foresee, such as glial differentiation, axogenesis, synaptic transmission, postsynaptic potential, and neuronal and glial migration. Immunodetection analysis demonstrated that Prl significantly modified microglial morphology, reduced the expression of Cd11b/c protein, and altered the content and location of the neuronal proteins Tau, Map2 and Syp, which are involved in axogenic and synaptic functions. This novel delineation of Prl activity in the hippocampus highlights its importance as a neuroactive hormone, opens a new avenue for understanding its actions and supports its participation in neuronal plasticity of this brain area.
2019-10-09 | GSE119435 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas.
2012-05-01 | GSE32387 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
2012-04-30 | E-GEOD-32387 | biostudies-arrayexpress
Project description:Primary afferent pathophysiology is thought to be a key driver in painful conditions, with dorsal root ganglia (DRG) neurons being well described for their role in driving both acute and chronic pain. These neurons encompass a diverse collection of subtypes that are grouped by various factors, each intrinsically related. These include size, myelination, conduction velocity, projection patterns, end organs, and general function. More recently, these subpopulations have been well documented through single cell and single nuclear RNA-seq in mice and human. This diversity is lost during bulk RNA-seq, due to the consolidation of all subtypes together. In single cell datasets, pseudo-bulk samples can be generated for each cluster, but this relies on a well-defined clustering that can be lost after nerve injury. As such, changes at a subtype level remain unclear in painful states. Here, we address this gap through the deep transcriptional profiles of multiple murine DRG populations in acute and chronic pain states while considering sex differences. We have studied the molecular changes in five populations: Scn10a-expressing DRG, peptidergic and non-peptidergic nociceptors, as well as C-LTMRs and Ntrk2-expressing A-LTMRs. In a naive state, we find subtype specific sexual dimorphism in a small number of genes. This does not translate to a strong interaction of sex and injury, as the injury response seems to be consistent across sexes at the neuronal transcript level. We also see both stereotypes and unique subpopulation signatures in injured states after nerve injury at both an acute (3 day) and chronic (4 week) timepoint, with notable changes in C-LTMR and NP populations, as well as a distinct transcriptional program in AB-RA + Ad-LTMRs by 4 weeks compared to the other subtypes in the study. This data has been deposited in a searchable database to increase accessibility at https://livedataoxford.shinyapps.io/drg-directory/.
2022-10-29 | GSE216444 | GEO
Project description:Pancreatic islets adapt to insulin resistance of pregnancy by up regulating beta-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr+/-) mice are glucose intolerant, had a lower number of beta cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its beta-cell-specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, i.e. bPrlR-/- mice, allowing conditional deletion of Prlr from beta cells in adult mice. In this study, we found that beta-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mice with global Prlr reduction, beta-cell-specific Prlr loss led to a lower beta-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus beta-cell-specific Prlr reduction, we found differences in expression of genes that regulate apoptosis, synaptic vesicle function and neuronal development. Indeed, islets from pregnant Prlr+/- mice are more susceptible glucolipotoxicity than bPrlR+/- islets. These observations suggest that Prlr has both cell-autonomous and non-cell-autonomous effect on beta cells, beyond its regulation of pro-proliferative genes.
2020-08-25 | GSE156774 | GEO
Project description:Aim: PROLACTIN (PRL), normally produced by the pituitary gland, acts through its receptor (PRL-R) to initiate a signalling cascade to the genome. PRL can also be produced by cancer cells and become oncogenic by stimulating its receptor following an autocrine or paracrine route. Here we investigated the oncogenic activities of PRL in lung cancer. Results: PRL is ectopically activated in a subset of very aggressive lung tumours, associated with a rapid fatal outcome, in our cohort of 293 lung tumour patients as well as in an external independent series of patients. An investigation of the molecular basis of PRL adverse effects surprisingly showed an absence of PRL-R expression in the vast majority of PRL-expressing lung tumours. Additionally, a detailed analysis of the ectopically expressed PRL transcripts in lung tumours and cell lines revealed systematic alterations of its first exons encoding the signal peptide. Finally, the transcriptomes of two PRL expressing lung cancer cell lines, with or without silencing of PRL, showed that PRL directly or indirectly sustains the expression of a group of genes that are frequently up-regulated in a variety of unrelated cancers. Interestingly, the gene signature repressed by PRL ectopic expression in lung tumour cells is also specifically up-regulated by HDAC inhibitor treatment or HDAC1/2/3 knock-down. Innovation and conclusion: Altogether, this work sheds lights on the poorly understood impact of the recently-shown large-scale out-of-context gene activity in cancer and also suggests that PRL-expressing aggressive lung cancers could be particularly responsive to a HDAC inhibitor-based treatment.
2014-08-05 | GSE49544 | GEO
Project description:Aim: PROLACTIN (PRL), normally produced by the pituitary gland, acts through its receptor (PRL-R) to initiate a signalling cascade to the genome. PRL can also be produced by cancer cells and become oncogenic by stimulating its receptor following an autocrine or paracrine route. Here we investigated the oncogenic activities of PRL in lung cancer. Results: PRL is ectopically activated in a subset of very aggressive lung tumours, associated with a rapid fatal outcome, in our cohort of 293 lung tumour patients as well as in an external independent series of patients. An investigation of the molecular basis of PRL adverse effects surprisingly showed an absence of PRL-R expression in the vast majority of PRL-expressing lung tumours. Additionally, a detailed analysis of the ectopically expressed PRL transcripts in lung tumours and cell lines revealed systematic alterations of its first exons encoding the signal peptide. Finally, the transcriptomes of two PRL expressing lung cancer cell lines, with or without silencing of PRL, showed that PRL directly or indirectly sustains the expression of a group of genes that are frequently up-regulated in a variety of unrelated cancers. Interestingly, the gene signature repressed by PRL ectopic expression in lung tumour cells is also specifically up-regulated by HDAC inhibitor treatment or HDAC1/2/3 knock-down. Innovation and conclusion: Altogether, this work sheds lights on the poorly understood impact of the recently-shown large-scale out-of-context gene activity in cancer and also suggests that PRL-expressing aggressive lung cancers could be particularly responsive to a HDAC inhibitor-based treatment. Total RNA was extracted from two small cell lung carcinoma (SCLC) cell lines expressing PRL (H146 and h524: si control) or not (siPRL) and the differentially expressed genes. Five replicates were analysed for each of the four conditions.
2014-08-05 | E-GEOD-49544 | biostudies-arrayexpress
Project description:Emerging evidence suggests that estrogen and prolactin (PRL) play a key role in prostate cancer development, yet their relationship and molecular actions in prostate is not well understood. To address this issue, we made the first direct comparison of estrogen and PRL actions in the Noble rat (NBL) prostate dysplasia model. Prostatic dysplasia in lateral prostate (DLP) has been induced by elevated circulating levels of estrogen and PRL in NBL with estrogen (E2)-filled implants, while physiological level of testosterone (T) was maintained with T-filled implants. The effect of estrogen and PRL was studied by using ICI and bromocriptine (Br) as their respective blockers, both can effectively inhibited dysplasia development under T+E2 induction. Transcript expression profile of the four treatment groups (Control, T+E2, T+E2+Br, and T+E2+ICI) has been characterized in this array.
2010-05-09 | E-GEOD-17819 | biostudies-arrayexpress