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Bulk RNAseq analysis of dorsal root ganglia from global Nav1.7 knockout mice

ABSTRACT: We investigated changes in gene expression of dorsal root ganglia (DRG) isolated from global (pCAGG-CreER x Nav1.7 floxed) Nav1.7 knockout mice using bulk RNA sequencing. We found an upregulation of Penk and downregulation of Ceacam10 in Nav1.7 knockouts compared to controls, as well as other gene expression changes similar to those previously reported for Nav1.7 knockout mice (https://doi.org/10.1038/ncomms9967). We identified that genes selectively expressed in the C low-threshold mechanoreceptor (cLTMR) class of DRG neurons showed a general reduction in expression in Nav1.7 knockouts compared to littermate controls.

ORGANISM(S): Mus musculus

PROVIDER: GSE213826 | GEO | 2023/05/22

REPOSITORIES: GEO

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Single cell RNAseq analysis of dorsal root ganglia from global and cLTMR-specific Nav1.7 knockout mice

Project description:We investigated changes in gene expression and cell type abundance using single cell RNA sequencing of dorsal root ganglia (DRG) isolated from global (pCAGG-CreER x Nav1.7 floxed) and C-low threshold mechanoreceptor (cLTMR)-specific (Slc17a8-Cre x Nav1.7 floxed) Nav1.7 knockout mice. We identified a reduction in the fraction of cLTMRs and a concomitant emergence of a distinct cell cluster located closely to cLTMRs in the UMAP projection in global Nav1.7 knockout DRGs. This novel cell cluster expressed previously described cLTMR markers with distinct gene expression changes such as a downregulation of Ceacam10 and an upregulation of Penk expression. We further found that cLTMR-specifc knockout of Nav1.7 induced the same shift in cLTMR cells to a knockout-specific cluster with upregulated Penk expression.

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The molecular basis of analgesia in congenital insensitivity to pain associated with loss of Nav1.7 function

Project description:Loss of function mutations in the SCN9a gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain (CIP) and anosmia in otherwise normal humans and mice, suggesting that this channel may be a good analgesic drug target. Surprisingly, potent selective antagonists of Nav1.7 are weak analgesics. We therefore investigated whether Nav1.7 , as well as contributing to electrical signalling may have an additional function. Here we report that Nav1.7 deletion has profound effects on the sensory neuron transcriptome, leading to dysregulation of a number of transcription factors as well as upregulation of enkephalin precursor PENK mRNA and down regulation of CEACAM10 mRNA, a protein involved in noxious thermosensation. PENK mRNA is transcriptionally upregulated in Nav1.7 null mutant female sensory neurons, resulting in increased enkephalin expression in the dorsal horn of the spinal cord. PENK expression is down-regulated by addition of the sodium ionophore monensin, suggesting that sodium may play a role as a second messenger. Application of the opioid antagonist naloxone strongly enhances noxious peripheral input into the spinal cord, and dramatically reduces analgesia in both male and female Nav1.7 null mutant mice, as well as in human Nav1.7 null mutants. These data show that loss of Nav1.7 expression increases opioid drive over the lifetime of mice and humans. They further suggest that Nav1.7 channel blockers alone may not replicate the phenotype of null mutant humans and mice, but should be potentiated with exogenous opioids. RNA was extracted from Dorsal Root Ganglia tissue from Nav1.7 Knock-Out, Nav1.8 KO and Nav1.9 KO mice (n = 3) and hybridised on Affymetrix Mouse Genome 430 2.0 Array (GPL1261)

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The molecular basis of analgesia in congenital insensitivity to pain associated with loss of Nav1.7 function

2014-09-13 | GSE61373 | GEO

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2022-01-01 | GSE159818 | GEO

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2018-01-15 | PXD005155 | Pride

RNAseq analysis of dorsal root ganglia from global Nav1.7 knockout mice

Project description:RNAseq analysis of dorsal root ganglia from global Nav1.7 knockout mice

| PRJNA882496 | ENA

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Project description:Mice and humans who have lost the expression of functional sodium channel Nav1.7 are pain-free, but otherwise normal. This is the result of a loss of neurotransmitter release such as glutamate and Substance P from primary sensory neurons. The sensory neurons are otherwise normal apart from loss of neurotransmitter release. Adult gene deletion results in a loss of neuronal excitability with some analgesia that is not linked to opioid activity. Drugs that block Nav1.7 have lethal effects through action on the autonomic nervous system and the heart. But the embryonic null humans and mice are fine. Therefore there must be compensation for the embryonic loss of Nav1.7. This experiment compares the protein components of wild type normal mice and Nav1.7 embryonic deletion mice in order to identify compensatory mechanisms.

2024-10-17 | PXD052513 | Pride

Bulk RNAseq analysis of dorsal root ganglia from global Nav1.7 knockout mice

Project description:Bulk RNAseq analysis of dorsal root ganglia from global Nav1.7 knockout mice

| PRJNA882499 | ENA

Single-cell gene expression profiles of hESC-derived retinal organoid progenitor cells and photoreceptor precursors from deep full-length scRNA-seq.

Project description:Human retinal organoids have been invaluable in vitro models of retinal development and disease. To investigate whether cell states and gene expression changes observed in human fetal cone development are accurately replicated in organoids, we produced H9 hESC-derived retinal organoids using two published methods (Kuwahara et al. 2015, Nat Comm 6, 6286, https://doi.org/10.1038/ncomms7286; Zhong et al. 2014, Nat Comm 5, 4047, https://doi.org/10.1038/ncomms5047). We then FACS-enriched cone and rod precursors and retinal progenitor cells every two weeks from 55-140 DIC, as well as at 225 DIC, and performed deep, full-length scRNA-seq chemistry. These data were used to identify maturation differences related to the organoid production method, identify aberrant cell populations or gene expression timing relative to human fetal retina, and define cone and rod photoreceptor trajectories in the retinal organoid setting.

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