Cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 23, 2023

Sensory neurons of the dorsal root ganglion (DRG) are critical for maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies DRGs conducted in rodents, much less is known about mechanisms sensory perception primates. We generated a transcriptome atlas mouse, guinea pig, cynomolgus monkey, human implementing common laboratory workflow multiple data-integration approaches generate high-resolution cross-species mappings neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related inflammatory response. also divergent expression key genes involved DRG function, suggesting species-specific adaptations specifically nociceptors that likely point function nociceptors. Among these, validated TAFA4, member druggable genome, was expressed distinct populations across species, programs therapeutic development.

Язык: Английский

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Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

Science Advances, Год журнала: 2024, Номер 10(25)

Опубликована: Июнь 21, 2024

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal (TG) are specialized to detect transduce diverse environmental stimuli central nervous system. Single-cell RNA sequencing has provided insights into diversity of sensory ganglia cell types rodents, nonhuman primates, humans, but it remains difficult compare across studies species. We thus constructed harmonized atlases DRG TG that describe facilitate comparison 18 neuronal 11 non-neuronal six species 31 datasets. then performed single-cell/nucleus from both human highly regenerative axolotl found atlas also improves type annotation, particularly sparse subtypes. observed transcriptomes neuron subtypes broadly similar vertebrates, expression functionally important neuropeptides channels can vary notably. The resources presented here guide future comparative transcriptomics, simplify cell-type nomenclature differences studies, help prioritize targets for analgesic development.

Язык: Английский

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Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model

Science, Год журнала: 2024, Номер 385(6704), С. 80 - 86

Опубликована: Июль 4, 2024

Classical migraine patients experience aura, which is transient neurological deficits associated with cortical spreading depression (CSD), preceding headache attacks. It not currently understood how a pathological event in cortex can affect peripheral sensory neurons. In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing nonsynaptic signaling between brain and cells. After CSD, ~11% of CSF proteome altered, up-regulation proteins directly activate receptors ganglion. collected from animals exposed to CSD activates neurons naïve mice part by CSF-borne calcitonin gene-related peptide (CGRP). We identify communication pathway central nervous system might explain relationship migrainous aura headache.

Язык: Английский

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Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes

Pain, Год журнала: 2025, Номер 166(3), С. 614 - 630

Опубликована: Янв. 23, 2025

Abstract Cell states are influenced by the regulation of gene expression orchestrated transcription factors capable binding to accessible DNA regions. To uncover if sex differences exist in chromatin accessibility human dorsal root ganglion (hDRG), where nociceptive neurons innervating body found, we performed bulk and spatial assays for transposase-accessible technology followed sequencing (ATAC-seq) from organ donors without a history chronic pain. Using ATAC-seq, detected abundant hDRG. In women, differentially regions (DARs) mapped mostly X chromosome, whereas men, they autosomal genes. Hormone-responsive factor motifs such as EGR1/3 were within DARs while JUN, FOS, other activating protein 1 enriched suggesting higher activation state cells compared with women. These observations consistent ATAC-seq data. Furthermore, validated that EGR1 is biased female hDRG using RNAscope. neurons, revealed GABAergic, glutamatergic, interferon-related genes women Ca 2+ -signaling-related men. Strikingly, XIST, responsible inactivating chromosome compacting it maintaining at periphery nucleus, was found be highly dispersed neuronal nuclei. This likely related observed both approaches. We have documented baseline epigenomic which provide important descriptive information test future hypotheses.

Язык: Английский

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Machine learning-driven identification of critical gene programs and key transcription factors in migraine

The Journal of Headache and Pain, Год журнала: 2025, Номер 26(1)

Опубликована: Янв. 20, 2025

Migraine is a complex neurological disorder characterized by recurrent episodes of severe headaches. Although genetic factors have been implicated, the precise molecular mechanisms, particularly gene expression patterns in migraine-associated brain regions, remain unclear. This study applies machine learning techniques to explore region-specific profiles and identify critical programs transcription linked migraine pathogenesis. We utilized single-nucleus RNA sequencing (snRNA-seq) data from 43 along with genome-wide association (GWAS) data, investigate susceptibility migraine. The cell-type-specific (CELLEX) algorithm was employed calculate specific for each region, while non-negative matrix factorization (NMF) applied decompose within single-cell these regions. Following annotation region genome, we stratified linkage disequilibrium score regression (S-LDSC) assess associations between programs, migraine-related SNPs. Key regulating were identified using random forest model based on regulatory networks derived GTEx consortium. Our analysis revealed significant enrichment single nucleotide polymorphisms (SNPs) posterior nuclear complex-medial geniculate nuclei (PoN_MG) thalamus, highlighting this region's crucial role Gene program 1, through NMF, enriched calcium signaling pathway, known contributor pathophysiology. Random predicted ARID3A as top factor suggesting its potential modulating calcium-related genes involved provides new insights into mechanisms underlying migraine, emphasizing importance PoN_MG thalamic pathways, key like ARID3A. These findings offer avenues developing targeted therapeutic strategies treatment.

Язык: Английский

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Persistent nociceptor hyperactivity as a painful evolutionary adaptation

Trends in Neurosciences, Год журнала: 2023, Номер 46(3), С. 211 - 227

Опубликована: Янв. 5, 2023

Язык: Английский

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Meningeal Mechanisms and the Migraine Connection

Annual Review of Neuroscience, Год журнала: 2023, Номер 46(1), С. 39 - 58

Опубликована: Март 13, 2023

Migraine is a complex neurovascular pain disorder linked to the meninges, border tissue innervated by neuropeptide-containing primary afferent fibers chiefly from trigeminal nerve. Electrical or mechanical stimulation of this nerve surrounding large blood vessels evokes headache patterns as in migraine, and brain, blood, meninges are likely sources triggers. Cerebrospinal fluid may play significant role migraine transferring signals released brain overlying pain-sensitive meningeal tissues, including dura mater. Interactions between afferents, neuropeptides, adjacent cells tissues cause neurogenic inflammation, critical target for current prophylactic abortive therapies. Here we review importance cranial headaches, explore properties briefly emerging concepts, such neuroimmune interactions, that one day prove therapeutically relevant.

Язык: Английский

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Sensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 20, 2023

Abstract Mesenchymal stem cells (MSCs) reside in microenvironments, referred to as niches, which provide structural support and molecular signals. Sensory nerves are niche components the homeostasis of tissues such skin, bone marrow hematopoietic system. However, how sensory nerve affects behavior MSCs remains largely unknown. Here we show that is vital for mesenchymal tissue maintenance continuously growing adult mouse incisor. Loss innervation leads disorder a decrease MSCs. Mechanistically, FGF1 from directly acts on by binding FGFR1 activates mTOR/autophagy axis sustain Modulation restores rescues Fgfr1 mutant mice. Collectively, our study provides insights into role regulation MSC mechanism governing it.

Язык: Английский

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Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 5, 2023

Abstract Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal (TG) are specialized to detect transduce diverse environmental stimuli including touch, temperature, pain central nervous system. Recent advances single-cell RNA-sequencing (scRNA-seq) have provided new insights into diversity of ganglia cell types rodents, non-human primates, humans, but it remains difficult compare transcriptomically defined across studies species. Here, we built cross-species harmonized atlases DRG TG that describe 18 neuronal 11 non-neuronal 6 species 19 studies. We then demonstrate utility this reference atlas by using annotate newly profiled nuclei/cells from both human highly regenerative axolotl. observe transcriptomic profiles neuron subtypes broadly similar vertebrates, expression functionally important neuropeptides channels can vary notably. The resources data presented here guide future comparative transcriptomics, simplify type nomenclature differences studies, help prioritize targets for therapy development.

Язык: Английский

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Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis

Journal of Clinical Investigation, Год журнала: 2024, Номер unknown

Опубликована: Март 26, 2024

G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here we report that Gpr37l1/GRP37L1 ranks among the most highly expressed transcripts in mouse and human dorsal root ganglia (DRGs), selectively satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) paclitaxel (PTX) led to reduced GPR37L1 expression on plasma membrane DRGs. Transgenic mice Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX STZ-induced pain, whereas overexpression DRGs reversed pain. co-expressed potassium channels, including KCNJ10 (Kir4.1) SGCs both KCNJ3 (Kir3.1) SGCs. regulates surface function channels. Notably, pro-resolving lipid mediator maresin (MaR1) serves as a ligand enhances or KCNJ3-mediated influx through GPR37L1. Chemotherapy suppressed SGCs, which MaR1 rescued Finally, genetic analysis revealed GPR37L1-E296K variant increased chronic risk destabilizing protein impairing protein's function. Thus, offers new therapeutic target for protection

Язык: Английский

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