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The complete molecular atlas of adult C. elegans glia across sexes

ABSTRACT: A comprehensive mechanistic understanding of nervous system function requires molecular insight into the diversity and sex dimorphism of both its component cell types: glia and neurons. Here, we present a single nuclear RNA-seq atlas of all glia of the adult C. elegans nervous system, across both sexes. Through computational modeling and in vivo validation, we identify molecular markers that separate anatomically distinct glia, and molecular heterogeneity within anatomically identical glia, which together imply extensive functional heterogeneity. We report that different glia are variably sexually dimorphic. And, we also define glial subclass and pan-glial molecular signatures. Finally, this global profiling uncovers that adult C. elegans glia do not use canonical dense core vesicle release machinery to release glial neuropeptides. Thus, complementing the existing single-cell neuron atlas and mapped connectome in C. elegans, this atlas (wormglia.org) now enables a complete and unprecedented single-cell and molecular insight of glia, and thereby, the nervous system of an adult metazoan.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE256266 | GEO | 2025/02/21

REPOSITORIES: GEO

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Project description:BACKGROUND Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS With ~4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glia reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.

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The complete molecular atlas of adult C. elegans glia across sexes

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