Sensory neurons display cell-type specific vulnerability to loss of axon-glia interactions
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205461 | GEO | 2022/06/06
REPOSITORIES: GEO
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Project description:PNS injuries initiate transcriptional changes in glial cells and sensory neurons that promote axonal regeneration. While the factors that initiate the transcriptional changes in glial cells are well characterized, the full range of stimuli that initiate the response of sensory neurons remain elusive. Here, using a genetic model of glial cell ablation, we find that glial cell loss results in transient PNS demyelination without overt axonal loss. By profiling sensory ganglia at single-cell resolution we show that glial cell loss induces a transcriptional injury response preferentially in proprioceptive and Aβ RA-LTMR neurons. The transcriptional response of sensory neurons to mechanical injury has been assumed to be a cell autonomous response. By identifying a similar response in non-injured, demyelinated neurons, our study suggests that this represents a non-cell autonomous transcriptional response of sensory neurons to the loss of axon-glial cell interactions.
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Project description:Sensory neurons display cell-type specific vulnerability to loss of axon-glia interactions
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Project description:Peripheral nervous system (PNS) injuries initiate transcriptional changes in glial cells and sensory neurons that promote axonal regeneration. While the factors that initiate the transcriptional changes in glial cells are well characterized, the full range of stimuli that initiate the response of sensory neurons remain elusive. Here, using a genetic model of glial cell ablation, we find that glial cell loss results in transient PNS demyelination without overt axonal loss. By profiling sensory ganglia at single-cell resolution, we show that glial cell loss induces a transcriptional injury response preferentially in proprioceptive and Aβ RA-LTMR neurons. The transcriptional response of sensory neurons to mechanical injury has been assumed to be a cell-autonomous response. By identifying a similar response in non-injured, demyelinated neurons, our study suggests that this represents a non-cell-autonomous transcriptional response of sensory neurons to glial cell loss and demyelination.
| S-EPMC9354470 | biostudies-literature
Project description:Sensory neurons display cell-type specific vulnerability to loss of neuron-glia interactions
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Project description:Satellite glia are the major glial type found in ganglia of the peripheral nervous system that wrap around cell bodies of sympathetic and sensory neurons that are very diverse. Other than their close physical association with peripheral neurons, little is known about this glial population. Here, we performed single cell RNA sequencing analysis and identified five different populations of satellite glia from sympathetic and sensory ganglia. We identify three shared populations of satellite glia enriched in immune-response genes, immediate-early genes and ion channels/ECM-interactors, respectively. Sensory- and sympathetic-specific satellite glia are differentially enriched for modulators of lipid metabolism. Sensory glia are also specifically enriched for genes involved in glutamate turnover. Further, satellite glia and Schwann cells can be distinguished by unique transcriptional signatures. This study reveals remarkable heterogeneity of satellite glia in the peripheral nervous system.
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Project description:Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with advanced virus- and genetic tracings, we have molecularly identified the 3 main types of PNs (Ia, Ib and II) and unexpectedly found that they segregate into 8 subgroups. Our data further reveal a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles, that together contribute to the sensory monitoring of complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later along with increased motor activity and show versatility in the adult following exercise training, suggesting adaptive proprioceptive function.
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Project description:The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world’s population suffers nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration and therefore, there are no available treatments. Familial Dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene ELP1. FD specifically affects the development and causes degeneration of the PNS. We previously employed patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin crosslinked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of YAP-dependent genes. Finally, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS), and in prefrontal cortical neurons (part of the central nervous system), in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes, and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.
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Project description:Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Investigating PNS NMPs we demonstrate their presence on the somata, proximal, and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP expressing DRGs are primarily MrgprA3+ and Cysltr2+. NMP inhibition in DRG cultures leads to cell autonomous and non-cell autonomous changes in Ca2+ signaling induced by KCl depolarization, ab-meATP, or the pruritogen histamine. Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain
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Project description:Pathologies of the central nervous system (CNS) white matter often result in permanent functional deficits because mature mammalian projection neurons fail to regenerate long-distance axons after injury. A major barrier to axonal regenerative research is that the CNS axons that regenerate in response to experimental treatments stall growth before reaching their post-synaptic targets. Here, we test the hypothesis that interaction of regenerating axons with live oligodendrocytes, which were absent during developmental axon growth, stalls axonal growth. To test this hypothesis, first, we used single cell RNA-seq (scRNA-seq) and immunohistological analysis to investigate whether post-injury born oligodendrocytes incorporate into the glial scar after optic nerve injury. Then, we administered demyelination-inducing cuprizone (used in studies of multiple sclerosis), concurrently with the stimulation of axon regeneration by Pten knockdown (KD) in projection neurons after optic nerve injury. We found that post-injury born oligodendrocyte lineage cells incorporate into the glial scar, where they are susceptible to the demyelination diet treatment, which reduced their presence in the glial scar. We further found that the demyelination diet enhanced Pten KD-stimulated axon regeneration, and localized injection of cuprizone promoted axon regeneration. We also present a website for comparing the gene expression of scRNA-seq-profiled optic nerve oligodendrocyte lineage cells under physiological and pathophysiological conditions. Annotation of oligodendrocyte lineage cell subtypes, and normal or injured condition, are indicated in the last two rows of the cell matrix CSV file.
2023-03-27 | GSE225410 | GEO
Project description:Induced sensory neurons (iSNs) generated from pluripotent stem cells are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for understanding human peripheral neuropathies.
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