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Sensory fibers of the peripheral nervous system carry sensation from specific sense structures or use different tissues and organs as receptive fields, and convey this information to the central nervous system. In the head of vertebrates, each cranial sensory ganglia and associated nerves perform specific functions. Sensory ganglia are composed of...
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Context 1
... known contribution to the gene regulatory network controlling the development of the different sensory ganglia in mouse is summarized in Figure 4. For some of these TF, mutations have been reported in human congenital diseases associated with sensory deficits ( Table 2). FIGURE 4 | Transcriptional regulatory networks controlling neurogenesis in mouse cranial sensory ganglia. ...Similar publications
Neuropathic pain is a severe and chronic condition widely found in the general population. The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients. During the processing of pain, the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a cru...
Sensory neurons are afferent neurons in sensory systems that convert stimuli and transmit information to the central nervous system as electrical signals. Primary afferent neurons that are affected by non-noxious and noxious stimuli are present in the dorsal root ganglia (DRG), and the DRG sensory neurons are used as an in vitro model of the nocice...
The vasculature is innervated by a network of peripheral afferents that sense and regulate blood flow. Here, we describe a system of non-peptidergic sensory neurons with cell bodies in the spinal ganglia that regulate vascular tone in the distal arteries. We identify a population of mechanosensitive neurons, marked by tropomyosin receptor kinase C...
Objective: Plexus injury results in lifelong suffering of flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts, such as cell replacement for restoring dorsal root ganglion (DRG) function, set high expectations. However, it is completely unclear which DRG cell types are affected by plexus i...
Prdm12 is an epigenetic regulator expressed in developing and mature nociceptive neurons, playing a key role in their specification during neurogenesis and modulating pain sensation at adulthood. In vitro studies suggested that Prdm12 recruits the methyltransferase G9a through its zinc finger domains to regulate target gene expression, but how Prdm...
Citations
... Inspired by the positive effects of exosomes on peripheral nerve regeneration, the figure illustrates the rejuvenating effect of exosomes on the peripheral nervous system the body and is basically classified into two parts: somatic and autonomic nervous systems [3]. The somatic nervous system includes motor and sensory neurons and is related to conscious activities, such as limb movements. ...
Peripheral nerve injuries (PNIs) are the term used to describe injuries that occur to the nerve fibers of the peripheral nervous system (PNS). Such injuries may be caused by trauma, infection, or aberrant immunological response. Although the peripheral nervous system has a limited capacity for self-repair, in cases of severe damage, this process is either interrupted entirely or is only partially completed. The evaluation of variables that promote the repair of peripheral nerves has consistently been a focal point. Exosomes are a subtype of extracellular vesicles that originate from cellular sources and possess abundant proteins, lipids, and nucleic acids, play a critical role in facilitating intercellular communication. Due to their modifiable composition, they possess exceptional capabilities as carriers for therapeutic compounds, including but not limited to mRNAs or microRNAs. Exosome-based therapies have gained significant attention in the treatment of several nervous system diseases due to their advantageous properties, such as low toxicity, high stability, and limited immune system activation. The objective of this review article is to provide an overview of exosome-based treatments that have been developed in recent years for a range of PNIs, including nerve trauma, diabetic neuropathy, amyotrophic lateral sclerosis (ALS), glaucoma, and Guillain-Barre syndrome (GBS). It was concluded that exosomes could provide favorable results in the improvement of peripheral PNIs by facilitating the transfer of regenerative factors. The development of bioengineered exosome therapy for PNIs should be given more attention to enhance the efficacy of exosome treatment for PNIs.
Graphical Abstract
Inspired by the positive effects of exosomes on peripheral nerve regeneration, the figure illustrates the rejuvenating effect of exosomes on the peripheral nervous system
... The trigeminal ganglion, a unique sensory ganglion, contains both motor and sensory neurons and receives two separate sets of sensory neuron precursors that contribute to the development of nociceptors, originating from both the neural crest (similar to dorsal root ganglia for peripheral nociceptors and pruriceptors) and trigeminal cranial placodes. 26 Whether PRDM12 regulates different transcription programmes in the trigeminal cranial placodes population, as has been shown for its downstream signal Brn3a, is unknown. 27 The MiTES phenotype strongly suggests that 18A mutation results in hyperexcitable pruriceptors, but only within the trigeminal ganglia. ...
Summary
Background: PRDM12 polyalanine tract expansions cause two different disorders; Midfacial Toddler Excoriation Syndrome (MiTES) - itch with normal pain sensation associated with homozygous 18 alanines (18A), and congenital insensitivity to pain (CIP) with normal itch with homozygous 19A. Knowledge of the phenotype, genotype, and disease mechanism of MiTES is incomplete. Why PRDM12 18A versus 19A can cause almost opposite phenotypes is unknown; no other poly-alanine or poly-glutamine tract expansion disease causes two such disparate phenotypes.
Methods
We assessed the genotype and phenotype of 9 new, 9 atypical, and 6 previously reported patients diagnosed with MiTES. Using cell lines with homozygous PRDM12 of 12A (normal), 18A (MiTES) and 19A (CIP) we examined PRDM12 aggregation and subcellular localisation by image separation confocal microscopy and sub-cellular fractionation western blotting.
Results
MiTES presents in the first year of life, and in all cases the condition regresses over the first decade leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12-CIP are rarely found. The genotype-phenotype study of PRDM12 polyalanine tract shows that 7A -15A are normal; 16A -18A are associated with MiTES; 19A leads to CIP; and no clinically atypical MiTES cases had an expansion. PRDM12 aggregation and sub-cellular localisation differ significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein aggregation disease.
Conclusion
We provide diagnostic criteria for MiTES, and improved longitudinal data. MiTES and CIP are distinct phenotypes despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells.. We hypothesise that the developmental environment of the trigeminal ganglion is unique and critically sensitive to prenatal and postnatal levels of PRDM12.
... These ganglia occupy a unique position, as they are the first station where sensory signals, including those of pain, are generated (Devor, 2013;Fuller et al., 2023;Raja et al., 2020). The main types of sensory ganglia are the dorsal root ganglia (DRGs), which innervate most parts of the body, including many internal organs (Vermeiren et al., 2020); and the trigeminal ganglia (TGs), which innervate the head, face and teeth (Chiang et al., 2011). Neurons in sensory ganglia are devoid of synapses, but possess numerous receptors for neurotransmitters and hormones. ...
Neurons in sensory ganglia are wrapped completely by satellite glial cells (SGCs). One putative function of SGCs is to regulate the neuronal microenvironment, but this role has received only little attention. In this study we investigated whether the SGC envelope serves a barrier function and how SGCs may control the neuronal microenvironment. We studied this question on short‐term (<24 h) cell cultures of dorsal root ganglia and trigeminal ganglia from adult mice, which contain neurons surrounded with SGCs, and neurons that are not. Using calcium imaging, we measured neuronal responses to molecules with established actions on sensory neurons. We found that neurons surrounded by SGCs had a smaller response to molecules such as adenosine triphosphate (ATP), glutamate, GABA, and bradykinin than neurons without glial cover. When we inhibited the activity of NTPDases, which hydrolyze the ATP, and also when we inhibited the glutamate and GABA transporters on SGCs, this difference in the neuronal response was no longer observed. We conclude that the SGC envelope does not hinder diffusional passage, but acts as a metabolic barrier that regulates the neuronal microenvironment, and can protect the neurons and modulate their activity.
... This neuronal diversity arises during development when specific transcriptional programs are initiated that bias the fate of neural crest-derived somatosensory progenitors into one of the three cardinal somatosensory lineages. These three main subtypes of somatosensory neurons can be discriminated early in development based on the selective expression of tyrosine kinase neurotrophic receptors [1][2][3][4]. Tyrosine kinase receptor A (TrkA)-is expressed in developing lightly or unmyelinated nociceptive neurons of small or medium diameter which mostly respond to noxious stimuli but are also involved in temperature or itch sensing [5] and in unmyelinated low-threshold mechanoreceptive (LTMR) neurons involved in pleasurable touch [6][7][8]. Ret, TrkB and TrkC are expressed in more myelinated LTMR neurons that convey innocuous touch sensation and proprioception. ...
... Over the last decades, a comprehensive understanding of the main transcriptional regulators guiding the early development and diversification of somatosensory neurons has been acquired. Notably, molecular players required for the emergence and diversification of the TrkA lineage have been identified [3,4]. Among them, the transcriptional regulator Prdm12 stands at the root of the specification of this lineage. ...
... Thus, in G9a cKO embryos, a transient increase of apoptosis appears to occur that however does not result in a dramatic loss of the nociceptive lineage, as observed in Prdm12 KO [11]. Phox2b is a master regulator of visceral fates in the peripheral nervous system [4,31,32]. As we recently discovered that Prdm12 also promotes nociceptor fate by repressing Phox2 genes and thus preventing precursors from engaging into an alternate visceral neuronal differentiation program [33], we also analyzed Phox2b expression in DRG of G9a cKO embryos. ...
Prdm12 is an epigenetic regulator expressed in developing and mature nociceptive neurons, playing a key role in their specification during neurogenesis and modulating pain sensation at adulthood. In vitro studies suggested that Prdm12 recruits the methyltransferase G9a through its zinc finger domains to regulate target gene expression, but how Prdm12 interacts with G9a and whether G9a plays a role in Prdm12’s functional properties in sensory ganglia remain unknown. Here we report that Prdm12-G9a interaction is likely direct and that it involves the SET domain of G9a. We show that both proteins are largely co-expressed in dorsal root ganglia during early murine development, opening the possibility that G9a plays a role in DRG and may act as a mediator of Prdm12’s function in the development of nociceptive sensory neurons. To test this hypothesis, we conditionally inactivated G9a in neural crest using a Wnt1-Cre transgenic mouse line. We found that the specific loss of G9a in the neural crest lineage does not lead to dorsal root ganglia hypoplasia due to the loss of somatic nociceptive neurons nor to the ectopic expression of the visceral determinant Phox2b as observed upon Prdm12 ablation. These findings suggest that Prdm12 function in the initiation of the nociceptive lineage does not critically involves its interaction with G9a.
... TG are in contrast of mixed origin. 5 How this somatic/visceral dichotomy is established in developing sensory neurons remains largely unknown. One transcription factor, however, stands out in this process, the evolutionarily conserved homeoprotein Phox2b that, together with its close relative Phox2a, act as determinants of visceral neuronal fate in both afferent pathways (as well as their targets in the hindbrain) and efferent autonomic pathways. ...
Prdm12 is a transcriptional regulator essential for the emergence of the somatic nociceptive lineage during sensory neurogenesis. The exact mechanisms by which Prdm12 promotes nociceptor development remain, however, poorly understood. Here, we report that the trigeminal and dorsal root ganglia hypoplasia induced by the loss of Prdm12 involves Bax-dependent apoptosis and that it is accompanied by the ectopic expression of the visceral sensory neuron determinants Phox2a and Phox2b, which is, however, not sufficient to impose a complete fate switch in surviving somatosensory neurons. Mechanistically, our data reveal that Prdm12 is required from somatosensory neural precursors to early post-mitotic differentiating nociceptive neurons to repress Phox2a/b and that its repressive function is context dependent. Together, these findings reveal that besides its essential role in nociceptor survival during development, Prdm12 also promotes nociceptor fate via an additional mechanism, by preventing precursors from engaging into an alternate Phox2 driven visceral neuronal type differentiation program.
... Adam11 knock-out mice show normal mechanical and noxious heat responses but have significantly decreased chemical nociception, indicating that Adam11 is necessary for the formation or the relay of specific set of sensory information (Takahashi et al., 2006a). The sensory neurons are derived mostly from the cranial placodes and cranial neural crest (cranial ganglia) anteriorly and from the trunk neural crest posteriorly (Vermeiren et al., 2020). The loss of specific type of nociception in Adam11 knock-out mice (Takahashi et al., 2006a) raises the possibility that the defect in these neurons might be a consequence of abnormal specification or migration of the neural crest. ...
Introduction: Cranial neural crest (CNC) cells are induced at the border of the neural plate by a combination of FGF, Wnt, and BMP4 signaling. CNC then migrate ventrally and invade ventral structures where they contribute to craniofacial development.
Methods: We used loss and gain of function experiments to determine phenotypes associated with the perturbation of Adam11 expression in Xenopus Laevis. Mass spectrometry to identify partners of Adam11 and changes in protein expression in CNC lacking Adam11. We used mouse B16 melanoma to test the function of Adam11 in cancer cells, and published database analysis to study the expression of ADAM11 in human tumors.
Results: Here we show that a non-proteolytic ADAM, Adam11, originally identified as a putative tumor suppressor binds to proteins of the Wnt and BMP4 signaling pathway. Mechanistic studies concerning these non-proteolytic ADAM lack almost entirely. We show that Adam11 positively regulates BMP4 signaling while negatively regulating β-catenin activity. In vivo, we show that Adam11 influences the timing of neural tube closure and the proliferation and migration of CNC. Using both human tumor data and mouse B16 melanoma cells, we further show that ADAM11 levels similarly correlate with Wnt or BMP4 activation levels.
Discussion: We propose that ADAM11 preserves naïve cells by maintaining low Sox3 and Snail/Slug levels through stimulation of BMP4 and repression of Wnt signaling, while loss of ADAM11 results in increased Wnt signaling, increased proliferation and early epithelium to mesenchyme transition.
... Meanwhile, L-sized trigeminal ganglion neurons have been recently suggested by the electrophysiological study that they can function as both nociceptive and non-nociceptive neurons 33 . Additionally, regarding electrophysiological properties, the fibers of SM-sized neurons often respond to high-intensity mechanical, thermal, and chemical stimuli, while the fibers of L-sized neurons function as low-threshold mechanoreceptors 34,35 . Understanding the differences in the properties of these neurons may provide new insights into the pathophysiology of migraine and potential therapeutic targets. ...
Migraine is a complex neurological disorder that affects millions of people worldwide. Despite extensive research, the underlying mechanisms that drive migraine pain and related abnormal sensation symptoms, such as hyperalgesia, allodynia, hyperesthesia, and paresthesia, remain poorly understood. One of the proposed mechanisms is cortical spreading depression (CSD), which is believed to be involved in the regulation of trigeminovascular pathways by sensitizing the pain pathway. Another mechanism is serotonin depletion, which is implicated in many neurological disorders and has been shown to exacerbate CSD-evoked pain at the cortical level. However, the effects of CSD and serotonin depletion on trigeminal ganglion neurons, which play a critical role in pain signal transmission, have not been thoroughly studied. In this study, we aimed to investigate the association between CSD and serotonin depletion with peripheral sensitization processes in nociceptive small-to-medium (SM) and large (L) -sized trigeminal ganglion neurons at the electrophysiological level using rat models. We divided the rats into four groups: the control group, the CSD group, the serotonin depletion group, and the CSD/serotonin depletion group. We induced CSD by placing KCl on a burr hole and serotonin depletion by intraperitoneal injection of PCPA (para-chlorophenoxyacetic acid). We then isolated trigeminal ganglion neurons from all groups and classified them according to size. Using patch-clamp recording, we recorded the excitability parameters and action potential (AP) properties of the collected neurons. Our results showed that in SM-sized trigeminal ganglion neurons, the CSD-SM and CSD/serotonin depletion groups had a higher positive resting membrane potential (RMP) than the control-SM group (p = 0.001 and p = 0.002, respectively, post-hoc Tukey’s test). In addition, the gap between RMP and threshold in the CSD-SM group was significantly narrower than in the control-SM group (p = 0.043, post-hoc Tukey’s test). For L-sized neurons, we observed prolongation of the AP rising time, AP falling time, and AP duration in neurons affected by CSD (p < 0.05, pairwise comparison test). In conclusion, our study provides new insights into the underlying mechanisms of migraine pain and abnormal somatosensation. CSD and serotonin depletion promote the transmission of pain signals through the peripheral sensitization process of nociceptive small-to-medium-sized trigeminal ganglion neurons, as well as nociceptive and non-nociceptive large-sized trigeminal ganglion neurons.
... 19,45 In addition to cranial placodes, cranial NCs contribute to sensory neurons as well as the sensory ganglia in cranial nerves I, II, V, VII, VIII, IX, X, and XI of the peripheral nervous system. 65,66 In addition, it has been shown that NC-derived cells can differentiate into endothelial cells when cultured in defined media. 51 Overall, our experiments analyzing the expression of Tuj-1, VEGFR2, and the Sox10-lineage reporter indicated that the loss of SMAD4 in the NC lineage did not expand the fate potential of NCs or cause aberrant migration of these cells. ...
Background
During embryogenesis, cardiac neural crest‐derived cells (NCs) migrate into the pharyngeal arches and give rise to the vascular smooth muscle cells (vSMCs) of the pharyngeal arch arteries (PAAs). vSMCs are critical for the remodeling of the PAAs into their final adult configuration, giving rise to the aortic arch and its arteries (AAAs).
Results
We investigated the role of SMAD4 in NC‐to‐vSMC differentiation using lineage‐specific inducible mouse strains. We found that the expression of SMAD4 in the NC is indelible for regulating the survival of cardiac NCs. Although the ablation of SMAD4 at E9.5 in the NC lineage led to a near‐complete absence of NCs in the pharyngeal arches, PAAs became invested with vSMCs derived from a compensatory source. Analysis of AAA development at E16.5 showed that the alternative vSMC source compensated for the lack of NC‐derived vSMCs and rescued AAA morphogenesis.
Conclusions
Our studies uncovered the requisite role of SMAD4 in the contribution of the NC to the pharyngeal arch mesenchyme. We found that in the absence of SMAD4⁺ NCs, vSMCs around the PAAs arose from a different progenitor source, rescuing AAA morphogenesis. These findings shed light on the remarkable plasticity of developmental mechanisms governing AAA development.
... Evolutionarily conserved TF-GRNs de ning Cber nociceptors, A-ber nociceptors, A-LTMRs, TRPM8, C-ber pruriceptors/nociceptors (hNP1, hNP2, hPEP.SST), and C-LTMRs were observed (yellow boxes in Fig. 2D) as well as species-speci c networks, such as for C-ber nociceptors, hTRPM8, hNP1, hNP2, hPEP.SST and hC.LTMR (green boxes in Fig. 2D). Among cross-species conserved transcriptional regulators, some were previously known to drive sensory neuron diversi cation in mouse, including ZEB2 in C-ber nociceptors 35 , SHOX2 in A-LTMRs 36,37 , RUNX3 in proprioceptors 38 , FOXP2 in TRPM8, RUNX1 in NP1 39 , ZNF52 and POU4F2 in C-LTMRs 16,40 . These transcription factors may contribute to the formation of different DRG neuron cell types and regulate the conserved and species-speci c gene expression in each cell population. ...
The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons – critical information to decipher their functions – are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the exist-ence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identify-ing high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma se-quencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-specific properties.
... Developmentally, cells of the nodose ganglia arise from two neurogenic niches: glial cells derive from the cranial neural crest while neurons derive from the epibranchial placode (Vermeiren et al., 2020). The differential contributions of the crest and placode were elucidated by a series of seminal quail-chick embryo transplantation studies where isotropic and isochronic grafts of quail crest or placode were transplanted into a chick host (Narayanan and Narayanan, 1980; Ayer-Le Lievre and Le Douarin, 1982;D'amico-Martel and Noden, 1983). ...
... In mice the viscerosensory nodose ganglia, i.e. inferior ganglia of the vagus nerve, are directly abutting the somatosensory jugular ganglia, i.e. superior ganglia of the vagus nerve. In contrast to the nodose ganglia, both neurons and glial cells of the jugular ganglia derive from the cranial neural crest (Vermeiren et al., 2020). Thus, the same neurogenic niche generates both jugular and nodose glial cells, but it is currently unknown whether there are molecular differences between nodose and jugular glial cell development. ...
The vagal ganglia, comprised of the superior (jugular) and inferior (nodose) ganglia of the vagus nerve, receive somatosensory information from the head and neck, or viscerosensory information from the inner organs, respectively. Developmentally, the cranial neural crest gives rise to all vagal glial cells and to neurons of the jugular ganglia, while the epibranchial placode gives rise to neurons of the nodose ganglia. Crest-derived nodose glial progenitors can additionally generate autonomic neurons in the peripheral nervous system, but how these progenitors generate neurons is unknown. Here, we found that some Sox10+ neural crest-derived cells in, and surrounding, the nodose ganglion transiently expressed Phox2b, a master regulator of autonomic nervous system development, during early embryonic life. Our genetic lineage tracing analysis revealed that despite their common developmental origin and extreme spatial proximity a substantial proportion of glial cells in the nodose, but not in the neighboring jugular ganglia, have a history of Phox2b expression. Lastly, we used single cell RNA-sequencing (scRNA-seq) to demonstrate that these progenitors give rise to all major glial subtypes in the nodose ganglia, including Schwann cells, satellite glia and glial precursors, and mapped their spatial distribution by in situ hybridization. Our work demonstrates that these crest- derived nodose glial progenitors transiently express Phox2b, give rise to the entire complement of nodose glial cells and display a transcriptional program that may underlie their bipotent nature.
Significance statement
The nodose ganglia contain sensory neurons that innervate many inner organs and play key roles in homeostatic behaviors such as digestion, regulation of blood pressure and heart rate, and breathing. Nodose sensory neurons are supported by nodose glial cells, which are understudied compared to their neuronal neighbors. Specifically, the genetic program governing their development is not fully understood. Here, we uncover a transcriptional program unique to nodose glial cells (transient expression of Phox2b) that resolves the 40-year-old finding that nodose glial progenitors can also give rise to autonomic neurons (whose development depends on Phox2b expression). Lastly, we leveraged single cell RNA-sequencing to identify the four major subtypes of nodose glial cells and used subtype specific marker genes to map their spatial distribution.
