Biology subjects

Cavalli, V.

Publications and source records attributed to Cavalli, V..

15 recordsLinked to original sources

bioRxiv2026

Single-Cell Atlas of Dorsal Root Ganglion Remodeling After Neuroma-Forming Nerve Injury Reveals Intervention-Specific Glial and Immune Programs

Peripheral nerve injury, whether caused by a cut, crush, or excessive stretch, can cause disordered regeneration and formation of a painful neuroma at the injury site. Regrowing axons may end in a swelling, hypersensitive nerve stump, producing pain along the affected nerve distribution that may outweigh sensory or motor deficits. Although neuromas are common, treatment outcomes are inconsistent and the mechanisms that initiate and sustain neuroma-associated pain remain poorly defined. Many surgical and non-surgical approaches (excision with transposition, capping, sclerosis, cryoablation) are used, yet comparative studies have not identified a superior technique, highlighting biological heterogeneity and knowledge gaps. A proximal nerve crush (axonotmetic injury) performed upstream of a neuroma or transection is proposed to reshape axonal growth and interrupt retrograde injury signaling, potentially shifting the system toward a more regenerative, pain-resolving state. However, how proximal crush remodels long-term programs in the dorsal root ganglion (DRG), and how these changes relate to neuroma-like outcomes, are unclear. Here, we build a single-cell atlas of DRG remodeling after neuroma-forming injury and compare it with two interventions- proximal nerve crush and nerve resection, using scRNA-seq. By resolving transcriptional responses across sensory neurons, satellite glial cells, Schwann cells, and macrophages, we identify intervention-specific glial and immune programs that distinguish permissive regeneration from persistent, pain-associated states and nominate pathways for mechanism-guided neuroma therapies.

neuroscience↗

bioRxiv2026

Satellite Glial Cells Control Sensory Neuron Excitability via the Release of Fibulin-2

Pain remains a major clinical challenge, with current therapies often limited by low efficacy and adverse effects. While excitability of sensory neurons in the dorsal root ganglia (DRG) is central to pain signaling, accumulating evidence highlights the importance of non-neuronal cells in modulating neuronal activity. Here, we identify satellite glial cells (SGCs) as a source of Fibulin-2, an extracellular matrix glycoprotein with diverse roles in nervous system development and repair. Using SGC primary cultures and mass spectrometry, we demonstrate that Fibulin-2 is secreted by SGCs in part via extracellular vesicles. Electrophysiological assays reveal that application of recombinant Fibulin-2 to cultured sensory neurons reduces neuronal excitability by modulating Kv4-mediated currents. In vivo, loss of Fibulin-2 leads to reduced Kv4.2 and Kv4.3 expression and heightened mechanical, heat and cold sensitivity in mice. Our findings uncover a SGC-sensory neuron signaling mechanism modulating pain sensitivity, suggesting Fibulin-2 as a potential therapeutic target for pain management.

neuroscience↗

bioRxiv2026

Single-cell transcriptomic atlas of glial cells in adult mouse dorsal root ganglia identifies multipotent progenitors

Sensory ganglia in the peripheral nervous system contain diverse glial populations that modulate sensory signaling, respond to injury and contribute to tissue homeostasis. Satellite glial cells (SGCs) surrounding neuronal soma in dorsal root ganglia (DRG) were suggested to retain developmental potential, but the identity of progenitor cells remains undefined. To capture glial diversity, we assembled a comprehensive single-cell transcriptomic atlas by integrating over 200,000 DRG and sciatic nerve transcriptomes across multiple studies and injury paradigms. High-resolution clustering resolved 28 cell types and demonstrated significant transcriptional heterogeneity within SGCs and Schwann cells, including repair and reactive sub-states. We identified two distinct populations of progenitor cells that reflect different states in the progenitor trajectory. Functionally, progenitor cell numbers increase after injury, and endothelin signaling regulates glial cell proliferation early in development. This integrated DRG and peripheral nerve atlas represents an essential resource for exploring new features of the peripheral nervous system.

neuroscience↗

bioRxiv2025

Single nucleus multiomic atlas of human dorsal root ganglia reveals the contribution of non-neuronal cell types to pain

Sensory neurons residing in dorsal root ganglia (DRG) transmit sensory information such as pain, itch, touch, pressure and bodily position to the central nervous system. The activity of sensory neurons is regulated by non-neuronal cell types in the DRG, including satellite glial cells (SGCs), immune cells and fibroblasts. Dysregulated gene expression in DRG cells contributes to sensory nervous system disorders such as chronic pain. Understanding the genetic underpinnings of these conditions requires dissecting transcriptional regulation in human tissue. In this study, we profiled transcriptomic and chromatin accessibility landscapes from postmortem human DRG (hDRG) samples at single-nucleus level. We demonstrate that sequencing depth significantly impacts downstream analysis, with deeper sequencing yielding more detected cells and features, improved data integration, refined clustering and annotation, and more accurate scientific interpretations. We identified nine major cell types, defined their molecular signatures, and mapped cis-regulatory landscapes. Integration of gene expression with chromatin accessibility enabled peak-gene association and transcriptional network analyses, revealing transcription factors, their target genes, regulatory elements and potential partners that cooperatively drive cell-type-specific gene expression programs. This integrative approach identified cell types, genes, and cis-regulatory regions potentially driving pain conditions. Our unbiased genome-wide analysis not only recovered known pain-related genes but also highlighted novel candidate genes and regulatory regions implicated in pain mechanisms. Importantly, our results demonstrate that non-neuronal cells, including endothelial cells, fibroblasts, macrophages, and SGCs, play critical roles in pain pathogenesis and should be investigated as therapeutic targets. One Sentence SummaryOur work provides a comprehensive single-nucleus multi-omic atlas of human dorsal root ganglia, uncovering novel cell-type-specific regulatory mechanisms and candidate therapeutic targets for pain, thereby directly advancing translational insights into human sensory disorders and chronic pain pathogenesis.

neuroscience↗

bioRxiv2025

A multi-omic atlas of human autonomic and sensory ganglia implicates cell types in peripheral neuropathies

The human peripheral nervous system (PNS) consists of many ganglia including sympathetic ganglia (SG) and dorsal root ganglia (DRG). These ganglia house the cell bodies of diverse PNS neurons that transmit autonomic and sensory signals, as well as a much larger number of non-neuronal cells. However, the molecular and cellular diversity of these human PNS cell types and their implications in human disease remain elusive. By generating an integrated single-cell multi-omic atlas of human SG and DRG, we provide comprehensive transcriptional and epigenomic landscapes of various cell types in these peripheral ganglia. While the major cell types and their cell-type-specific transcriptional and epigenomic features are similar between human SG and DRG, we identify key differences between SG and DRG cell types. These differences highlight the distinct molecular and cellular mechanisms underlying their specific functions. We also profiled key genomic regulatory networks that govern cell-type-specific gene expression in these peripheral ganglia. Moreover, by mapping the expression and chromatin accessibility of disease-associated genes in human SG and DRG, we identify cell types that may underlie various peripheral neuropathies. This atlas serves as a valuable resource for understanding the intricate cell-type-specific molecules and interactions in the human PNS and their implications in human health and diseases.

neuroscience↗

bioRxiv2025

Macrophage depletion restores the DRG microenvironment and prevents axon degeneration in bortezomib-induced neuropathy

Peripheral neuropathy is a common and debilitating side effect of the chemotherapeutic bortezomib (BTZ). To explore the mechanisms underlying BTZ-induced neuropathy (BIPN), we developed a mouse model that replicates the route of administration and approximates the prolonged BTZ exposure experienced by patients. We find that male mice treated with BTZ experience more severe sensorimotor dysfunction and axon loss compared to females and observed similar results when analyzing human data. Using single cell RNA-sequencing, we reveal that BTZ significantly alters the dorsal root ganglia (DRG) microenvironment in mice, producing pronounced sex-specific changes in satellite glial cells (SGCs) in males and females and dysregulation of the extracellular matrix (ECM), particularly in males. These changes are accompanied by expansion of macrophages, which is more pronounced in males. We identify four macrophage subtypes in the DRG, including a pro-fibrotic population that is exclusively associated with BIPN. Depletion of macrophages via anti-CSF1R treatment in male mice prevents BTZ-induced SGC activation and aberrant collagen deposition in DRGs, potently preserves peripheral axons, and improves functional outcomes. These findings highlight SGCs, neuroinflammation and dysregulation of the ECM as drivers of sex-specific differences in BIPN and suggest that targeting neuroinflammation is a promising therapeutic strategy to treat this disease. One Sentence SummaryInflammation and neurofibrosis in DRGs underlie sex-specific differences in bortezomib-induced neuropathy and are promising treatment targets.

neuroscience↗

bioRxiv2024

Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline

Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown. Using single cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron soma residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex-vivo in DRG explant cultures improves axon growth in both adult and aged conditions. In vivo, treatment with the FDA-approved compound, Bosentan, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment. These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies. One Sentence SummaryInhibition of endothelin signaling improves nerve regeneration after central and peripheral injuries and counters age-related regenerative decline.

neuroscience↗

bioRxiv2023

Circuit-based intervention corrects excessive dentate gyrus output in the Fragile X mouse model

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell hypo-excitability is caused by increased Kv7 function in Fmr1 KO mice. By reducing the excitatory drive onto local hilar interneurons, hypo-excitability of mossy cells results in increased excitation/inhibition ratio in granule cells and thus paradoxically leads to excessive dentate output. Circuit-wide inhibition of Kv7 channels in Fmr1 KO mice increases inhibitory drive onto granule cells and normalizes the dentate output in response to physiologically relevant theta-gamma coupling stimulation. Our study suggests that circuit-based interventions may provide a promising strategy in this disorder to bypass irreconcilable excitability defects in different cell types and restore their pathophysiological consequences at the circuit level.

neuroscience↗

bioRxiv2021

FKBPL and FKBP8 regulate DLK degradation and neuronal responses to axon injury

DLK is a key regulator of axon regeneration and degeneration in response to neuronal injury. To understand the molecular mechanisms controlling the DLK function, we performed yeast two-hybrid screening analysis and identified FKBPL as a DLK-binding protein that bound to the kinase domain and inhibited the kinase enzymatic activity of DLK. FKBPL regulated DLK stability through ubiquitin-dependent DLK degradation. We tested other members in the FKBP protein family and found that FKBP8 also induced DLK degradation as FKBPL did. We found that Lysine 271 residue in the kinase domain of DLK was a major site of ubiquitination and SUMO3-conjugation and responsible for FKBP8-mediated degradation. In vivo overexpression of FKBP8 delayed progression of axon degeneration and neuronal death following axotomy in sciatic and optic nerves, respectively, although axon regeneration efficiency was not enhanced. This research identified FKBPL and FKBP8 as new DLK-interacting proteins that regulated DLK stability by MG-132 or bafilomycin A1-sensitive protein degradation.

neuroscience↗

bioRxiv2021

Profiling the molecular signature of Satellite Glial Cells at the single cell level reveals high similarities between rodent and human

Peripheral sensory neurons located in dorsal root ganglia relay sensory information from the peripheral tissue to the brain. Satellite glial cells (SGC) are unique glial cells that form an envelope completely surrounding each sensory neuron soma. This organization allows for close bi-directional communication between the neuron and it surrounding glial coat. Morphological and molecular changes in SGC have been observed in multiple pathological conditions such as inflammation, chemotherapy-induced neuropathy, viral infection and nerve injuries. There is evidence that changes in SGC contribute to chronic pain by augmenting neuronal activity in various rodent pain models. SGC also play a critical role in axon regeneration. Whether findings made in rodent model systems are relevant to human physiology have not been investigated. Here we present a detailed characterization of the transcriptional profile of SGC in mouse, rat and human at the single cell level. Our findings suggest that key features of SGC in rodent models are conserved in human. Our study provides the potential to leverage rodent SGC properties and identify potential targets in humans for the treatment of nerve injuries and alleviation of painful conditions.

neuroscience↗

bioRxiv2021

Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration

Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote RGC axon regeneration, we identified transcription factors (TF) and chromatin accessible sites enriched in embryonic RGCs (high axon growth capacity) compared to postnatal RGC (low axon growth capacity). Developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the differentially opened regions of the chromatin in embryonic RGCs and proteomic analysis confirmed their expression in RGC nuclei. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon growth. Consistently, overexpression of CREB fused to the VP64 transactivation domain in RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.

neuroscience↗

bioRxiv2020

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for axon regeneration

Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPAR signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPAR agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease.

neuroscience↗

bioRxiv2020

Ascending dorsal column sensory neurons respond to spinal cord injury anddownregulate genes related to lipid metabolism

Regeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined specifically in injured sensory neurons. Using RNA sequencing of dorsal root ganglion, we determined that thoracic SCI elicits a transcriptional response distinct from sciatic nerve injury (SNI). Both SNI and SCI induced upregulation of ATF3 and Jun, yet this response failed to promote growth in sensory neurons after SCI. RNA sequencing of purified sensory neurons one and three days after injury revealed that unlike SNI, the SCI response is not sustained. Both SCI and SNI elicited the expression of ATF3 target genes, with very little overlap between conditions. Pathway analysis of differentially expressed ATF3 target genes revealed that fatty acid biosynthesis and terpenoid backbone synthesis were downregulated after SCI but not SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating palmitic acid, decreased axon growth and regeneration in vitro. These results supports the notion that decreased expression of lipid metabolism-related genes after SCI, including fatty acid synthase, may restrict axon regenerative capacity after SCI.

neuroscience↗

bioRxiv2019

Fatty acid synthesis in satellite glial cell promotes regenerative growth in sensory neurons

Peripheral sensory neurons switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, undergo injury-evoked transcriptional changes and contribute to nerve regeneration remains unexplored. This is largely due to the lack of molecular and genetic tools to study SGC. Using a single cell RNAseq approach to define the transcriptional profile of SGC in naive and injured conditions, we reveal that these cells are distinct from Schwann cells and share similarities with astrocytes. We find that nerve injury elicits gene expression changes in SGC, which are related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPAR) signaling. Conditional deletion of Fatty acid synthase (Fasn), the committed enzyme in de novo fatty acid synthesis, in SGC, impairs axon regeneration. The PPAR agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC, indicating that PPAR functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results identify fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in adult peripheral nerves. These results also highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair.

neuroscience↗

bioRxiv2019

Mechanism of microtubule plus-end tracking by the plant-specific SPR1 protein and its development as a versatile plus-end marker

The dynamics and functions of microtubule plus-ends are governed by microtubule plus-end tracking proteins (+TIPs). Here, we report that the diminutive Arabidopsis thaliana SPIRAL1 (SPR1) protein, which regulates directional cell expansion, is an autonomous +TIP. Using in vitro reconstitution experiments and total internal reflection fluorescence microscopy, we demonstrate that the conserved N-terminal domain of SPR1 and its GGG motif are necessary for +TIP activity, whereas the conserved C-terminal domain and its PGGG motif are not. In addition, we show that the N-and C-terminal domains, either separated or in tandem, are sufficient for +TIP activity and do not significantly perturb microtubule plus-end dynamics compared to full-length SPR1. We also found that exogenously expressed SPR1-GFP and NC-GFP label microtubule plus-ends in animal cells. These data establish SPR1 as a new type of intrinsic +TIP and demonstrate its utility as a universal microtubule plus-end marker.

cell biology↗