Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of Familial Dysautonomia

Familial Dysautonomia (FD) is a sensory and autonomic neuropathy caused by a mutation in Elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired perception of facial pain and temperature. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure comprised of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives (Elp1 CKO) are born with smaller trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate Elp1 expression in both neural crest- and placode-derived trigeminal neurons, which our data suggest give rise to primarily TrkA- and TrkB/C-expressing neurons, respectively. While Elp1 is not required for initial trigeminal ganglion formation, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and decreased target innervation. Developing nociceptors that express the receptor TrkA are especially vulnerable to Elp1 loss. TrkA expression is decreased in Elp1 CKO trigeminal nerve endings, coinciding with increased cell death. Subsequently, fewer TrkA neurons are present in the Elp1 CKO trigeminal ganglion, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. These findings explain the loss of facial pain and temperature sensation in FD.

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The Role of the Placodes in the Development of the Glossopharyngeal, Vagal, and Trigeminal Ganglia

Neurographics ◽

10.3174/ng.1900007 ◽

2020 ◽

Vol 10 (3) ◽

pp. 163-181

Author(s):

P.M. Som

Keyword(s):

Neural Crest ◽

Trigeminal Ganglion ◽

Cranial Nerves ◽

Present Review ◽

Trigeminal Ganglia ◽

Epibranchial Placodes ◽

Vagal Ganglia

The epibranchial placodes combine with the neural crest to form the inferior and superior ganglia of the glossopharyngeal and vagal cranial nerves, respectively. By comparison, the single trigeminal ganglion is composed of both neural crest and placodal cells. The steps that lead up to these events include gastrulation and the embryology of the notochord, neural crest, and the placodes. Each of these steps is reviewed in some detail. In previous reviews in this series, the embryology related to the olfactory, otic, and lens placodes, and to the geniculate ganglia has been discussed.1-3 However, the somewhat unusual embryology of the 2 ganglia of cranial nerves IX and X was only briefly mentioned as was the development of the trigeminal ganglion.4 This present review revisits these events and specifically focuses on how these ganglia develop.Learning Objective: The reader will learn the unusual development of the superior and inferior glossopharyngeal and the vagal ganglia as well as review the varied steps in the embryology that proceeds these events. By comparison, the development of the single trigeminal ganglion is presented and the differences in its development from that of the ganglia of cranial nerves IX and X are emphasized.

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Cadherin-7 mediates proper neural crest cell-placodal neuron interactions during trigeminal ganglia assembly

10.1101/434613 ◽

2018 ◽

Author(s):

Chyong-Yi Wu ◽

Lisa A. Taneyhill

Keyword(s):

Neural Crest ◽

Adherens Junctions ◽

Neural Crest Cell ◽

Neural Crest Cells ◽

Trigeminal Ganglia ◽

Cellular Interactions ◽

Cranial Neural Crest ◽

Trigeminal Neurons ◽

Cranial Neural Crest Cells ◽

Crest Cell

ABSTRACTThe cranial trigeminal ganglia play a vital role in the peripheral nervous system through their relay of sensory information from the vertebrate head to the brain. These ganglia are generated from the intermixing and coalescence of two distinct cell populations: cranial neural crest cells and placodal neurons. Trigeminal ganglia assembly requires the formation of cadherin-based adherens junctions within the neural crest cell and placodal neuron populations; however, the molecular composition of these adherens junctions is still unknown. Herein, we aimed to define the spatio-temporal expression pattern and function of Cadherin-7 during early chick trigeminal ganglia formation. Our data reveal that Cadherin-7 is expressed exclusively in migratory cranial neural crest cells and is absent from trigeminal neurons. Using molecular perturbation experiments, we demonstrate that modulation of Cadherin-7 in neural crest cells influences trigeminal ganglia assembly, including the organization of neural crest cells and placodal neurons within the ganglionic anlage. Moreover, alterations in Cadherin-7 levels lead to changes in the morphology of trigeminal neurons. Taken together, these findings provide additional insight into the role of cadherin-based adhesion in trigeminal ganglia formation, and, more broadly, the molecular mechanisms that orchestrate the cellular interactions essential for cranial gangliogenesis.

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Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity

Journal of Neurophysiology ◽

10.1152/jn.00167.2011 ◽

2012 ◽

Vol 108 (2) ◽

pp. 431-440 ◽

Cited By ~ 20

Author(s):

Oana Covasala ◽

Sören L. Stirn ◽

Stephanie Albrecht ◽

Roberto De Col ◽

Karl Messlinger

Keyword(s):

Trigeminal Ganglion ◽

Dura Mater ◽

Calcitonin Gene Related Peptide ◽

Afferent Input ◽

Nitric Oxide Donor ◽

Cgrp Receptor ◽

Related Peptide ◽

Trigeminal Neurons ◽

Calcitonin Gene ◽

Evoked Activity

Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. α-CGRP (10−5 M), the CGRP receptor antagonist olcegepant (10−3 M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 μg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion.

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Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

International Journal of Molecular Sciences ◽

10.3390/ijms21082938 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2938

Author(s):

Timea Aczél ◽

Angéla Kecskés ◽

József Kun ◽

Kálmán Szenthe ◽

Ferenc Bánáti ◽

...

Keyword(s):

Gene Expression ◽

Glial Cells ◽

Orofacial Pain ◽

Model Potential ◽

Trigeminal System ◽

Trigeminal Ganglia ◽

Peripheral Sensitization ◽

Satellite Glial Cells ◽

Pain Model ◽

Nociceptive Neurons

A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund’s adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4-/- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system.

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Endomorphin-1 and Endomorphin-2 Modulate Responses of Trigeminal Neurons Evoked by N-Methyl-d-Aspartic Acid and Somatosensory Stimuli

Journal of Neurophysiology ◽

10.1152/jn.2000.83.6.3570 ◽

2000 ◽

Vol 83 (6) ◽

pp. 3570-3574 ◽

Cited By ~ 6

Author(s):

Xiao-Min Wang ◽

Kai-Ming Zhang ◽

Layron O. Long ◽

Carmina A. Flores ◽

Sukhbir S. Mokha

Keyword(s):

Dorsal Horn ◽

Opioid Receptor ◽

Inhibitory Effect ◽

Noxious Stimulus ◽

Evoked Responses ◽

Natural Stimulus ◽

Nociceptive Neurons ◽

Medullary Dorsal Horn ◽

Trigeminal Neurons ◽

Μ Opioid Receptor

The present study investigated the modulation of N-methyl-d-aspartate (NMDA)-evoked and peripheral cutaneous stimulus-evoked responses of trigeminal neurons by endomorphins, endogenous ligands for the μ-opioid receptor. Effects of endomorphins, administered microiontophoretically, were tested on the responses of nociceptive neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized rats. Endomorphin-1 and endomorphin-2 predominantly reduced the NMDA-evoked responses, producing an inhibitory effect of 54.1 ± 2.96% (mean ± SE; n = 34, P < 0.001) in 92% (34/37) of neurons and 63.6 ± 3.61% ( n = 32, P< 0.001) in 91% (32/35) of neurons, respectively. The inhibitory effect of endomorphins was modality specific; noxious stimulus-evoked responses were reduced more than nonnoxious stimulus-evoked responses. Naloxone applied at iontophoretic current that blocked the inhibitory effect of [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, reduced the peak inhibitory effect of endomorphins on the NMDA- and natural stimulus-evoked responses. We suggest that endomorphins by acting at μ-opioid receptor selectively modulate noxious stimulus-evoked responses in the medullary dorsal horn.

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Programming Parameters and Techniques in Trigeminal Ganglion Stimulation for Intractable Facial Pain

Neuromodulation Technology at the Neural Interface ◽

10.1111/ner.13306 ◽

2020 ◽

Author(s):

Kunal Gupta ◽

Pavlos Texakalidis ◽

Nicholas M. Boulis

Keyword(s):

Trigeminal Ganglion ◽

Facial Pain

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Neuropilin 2/semaphorin 3F signaling is essential for cranial neural crest migration and trigeminal ganglion condensation

Journal of Neurobiology ◽

10.1002/neu.20326 ◽

2007 ◽

Vol 67 (1) ◽

pp. 47-56 ◽

Cited By ~ 4

Author(s):

Laura S. Gammill ◽

Constanza Gonzalez ◽

Marianne Bronner-Fraser

Keyword(s):

Neural Crest ◽

Trigeminal Ganglion ◽

Cranial Neural Crest ◽

Semaphorin 3F ◽

Neural Crest Migration

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Induction and Inhibition of Apoptosis by Pseudorabies Virus in the Trigeminal Ganglion during Acute Infection of Swine

Journal of Virology ◽

10.1128/jvi.75.1.469-479.2001 ◽

2001 ◽

Vol 75 (1) ◽

pp. 469-479 ◽

Cited By ~ 32

Author(s):

Nuria Alemañ ◽

Marı́a Isabel Quiroga ◽

Mónica López-Peña ◽

Sonia Vázquez ◽

Florentina H. Guerrero ◽

...

Keyword(s):

Trigeminal Ganglion ◽

Pseudorabies Virus ◽

Acute Infection ◽

Light And Electron Microscopy ◽

Inflammatory Cells ◽

Trigeminal Ganglia ◽

Morphological Studies ◽

Infected Cells ◽

Induced Apoptosis

ABSTRACT We examined the ability of pseudorabies virus (PRV) to induce and suppress apoptosis in the trigeminal ganglion during acute infection of its natural host. Eight pigs were intranasally inoculated with a virulent field strain of PRV, and at various early times after inoculation, the trigeminal ganglia were assessed histologically. PRV-infected cells were detected by use of immunohistochemistry and in situ hybridization, and apoptosis was identified by in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. Light and electron microscopy was also used for morphological studies. Apoptosis was readily detected among infiltrating immune cells that were located surrounding PRV-infected neurons. The majority of PRV-infected neurons did not show morphological or histochemical evidence of apoptosis, even including those neurons that were surrounded by numerous inflammatory cells and exhibited profound pathological changes. However, neuronal virus-induced apoptosis also occurred but at a sporadic low level. These findings suggest that PRV is able to block apoptosis of infected trigeminal ganglionic neurons during acute infection of swine. Furthermore, our results also suggest that apoptosis of infiltrating inflammatory cells may represent an important viral mechanism of immune evasion.

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Molecular basis of tactile specialization in the duck bill

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1708793114 ◽

2017 ◽

Vol 114 (49) ◽

pp. 13036-13041 ◽

Cited By ~ 11

Author(s):

Eve R. Schneider ◽

Evan O. Anderson ◽

Marco Mastrotto ◽

Jon D. Matson ◽

Vincent P. Schulz ◽

...

Keyword(s):

Molecular Basis ◽

Expression System ◽

Inactivation Kinetics ◽

Trigeminal Ganglia ◽

Heterologous Expression System ◽

Activation Threshold ◽

Trigeminal Neurons ◽

Electrophysiological Characterization ◽

Sense Of Touch

Tactile-foraging ducks are specialist birds known for their touch-dependent feeding behavior. They use dabbling, straining, and filtering to find edible matter in murky water, relying on the sense of touch in their bill. Here, we present the molecular characterization of embryonic duck bill, which we show contains a high density of mechanosensory corpuscles innervated by functional rapidly adapting trigeminal afferents. In contrast to chicken, a visually foraging bird, the majority of duck trigeminal neurons are mechanoreceptors that express the Piezo2 ion channel and produce slowly inactivating mechano-current before hatching. Furthermore, duck neurons have a significantly reduced mechano-activation threshold and elevated mechano-current amplitude. Cloning and electrophysiological characterization of duck Piezo2 in a heterologous expression system shows that duck Piezo2 is functionally similar to the mouse ortholog but with prolonged inactivation kinetics, particularly at positive potentials. Knockdown of Piezo2 in duck trigeminal neurons attenuates mechano current with intermediate and slow inactivation kinetics. This suggests that Piezo2 is capable of contributing to a larger range of mechano-activated currents in duck trigeminal ganglia than in mouse trigeminal ganglia. Our results provide insights into the molecular basis of mechanotransduction in a tactile-specialist vertebrate.

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