Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs

Abstract

Two major types of nociceptors have been described in dorsal root ganglia (DRGs). In comparison, little is known about the vagal nociceptor subtypes. The vagus nerves provide much of the capsaicin-sensitive nociceptive innervation to visceral tissues, and are likely to contribute to the overall pathophysiology of visceral inflammatory diseases. The cell bodies of these afferent nerves are located in the vagal sensory ganglia referred to as nodose and jugular ganglia. Neurons of the nodose ganglion are derived from the epibranchial placodes, whereas jugular ganglion neurons are derived from the neural crest. In the adult mouse, however, there is often only a single ganglionic structure situated alone in the vagus nerve. By employing Wnt1Cre/R26R mice, which express β-galactosidase only in neural crest derived neurons, we found that this single vagal sensory ganglion is a fused ganglion consisting of both neural crest neurons in the rostral portion and non-neural crest (nodose) neurons in the more central and caudal portions of the structure. Based on their activation and gene expression profiles, we identified two major vagal capsaicin-sensitive nociceptor phenotypes, which innervated a defined target, namely the lung in adult mice. One subtype is non-peptidergic, placodal in origin, expresses P2X2 and P2X3 receptors, responds to α,β-methylene ATP, and expresses TRKB, GFRα1 and RET. The other phenotype is derived from the cranial neural crest and does not express P2X2 receptors and fails to respond to α,β-methylene ATP. This population can be further subdivided into two phenotypes, a peptidergic TRKA + and GFRα3 + subpopulation, and a non-peptidergic TRKB + and GFRα1 + subpopulation. Consistent with their similar embryonic origin, the TRPV1 expressing neurons in the rostral dorsal root ganglia were more similar to jugular than nodose vagal neurons. The data support the hypothesis that vagal nociceptors innervating visceral tissues comprise at least two major subtypes. Due to distinctions in their gene expression profile, each type will respond to noxious or inflammatory conditions in their own unique manner.

Sensory Nerve Terminal Mitochondrial Dysfunction Induces Hyperexcitability in Airway Nociceptors via Protein Kinase C

“…We therefore extended our study of mitochondrial modulation-induced hyperexcitability to determine its effects on bronchopulmonary C-fiber responses to chemical stimuli. Previous studies showed that the vast majority of mouse bronchopulmonary sensory nerves are activated by the selective P2X 2/3 agonist a,b-mATP and that this response is reproducible (Kollarik et al, 2003;Nassenstein et al, 2010). Consistent with these reports, 30 mM a,b-mATP activated .90% of bronchopulmonary C-fibers regardless of their conduction velocity or TRP channel expression.…”

“…We determined the action potential discharge response to a,b-methylene ATP (a,b-mATP; P2X 2/3 agonist, 30 mM) intratracheally applied as a 1-ml bolus over 10 seconds (Nassenstein et al, 2010). This submaximal dose is sufficient to activate all P2X 2/3 expressing bronchopulmonary C-fibers (Nassenstein et al, 2010). The lungs were then treated with antimycin A (20 mM) or other mitochondrial modulators.…”

Neurotrophin and GDNF family ligand receptor expression in vagal sensory nerve subtypes innervating the adult guinea pig respiratory tract

“…We are not aware of other studies comparing neurotrophin receptor expression in identified A-and C-fiber vagal sensory neurons. However, we recently evaluated the neurotrophin receptor expression in nodose and jugular ganglion C-fiber neurons innervating the mouse lungs and obtained data in agreement with those produced presently; the placodal C-fibers preferentially expressed TrkB, whereas the neural crest C-fibers preferentially expressed TrkA (40). The expression of TrkB by nodose neurons is also consistent with studies showing the developing nodose neurons in general often express TrkB and is dependent on BDNF for survival (57,59).…”

Purinergic Signaling in the Airways

“…Vagal C fibers innervating the pulmonary system are derived from cell bodies situated in both jugular (neural crest-derived) and nodose (placodal) vagal sensory ganglia. Only the nodose C-fiber population responds to P2X receptor activation Nassenstein et al, 2010). In addition, intrapulmonary myelinated nodose airway mechanosensors (A-fiber stretch receptors) have been reported to be activated by ATP via P2X receptors .…”