Abstract
Dorsal root ganglia (DRGs) contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury.
Highlights
Sensory modalities such as pain, touch and proprioception are relayed from the periphery to the spinal cord by somatosensory neurons located in the dorsal root ganglia (DRGs)
Western blot analysis on mouse adult DRGs revealed two bands identical to those observed in kidney protein extracts (Fig. 1B), indicating that the two FXYD2 isoforms are present in the DRGs
Our analysis reveals some aspects of the regulatory mechanism leading to the restricted expression of FXYD2 in the DRGs, notably in the non-peptidergic nociceptive neurons
Summary
Sensory modalities such as pain, touch and proprioception are relayed from the periphery to the spinal cord by somatosensory neurons located in the dorsal root ganglia (DRGs). These neurons constitute a heterogeneous neuronal population based on anatomical, functional, neurotrophin dependence and molecular criteria. We report the first description of FXYD2 expression in discrete neuronal sub-populations of the adult mouse DRGs, consisting in the TrkB-positive (+) mechanoceptors and the Ret+/IB4+ non-peptidergic nociceptors. In the latter population, Runx and Ret are required for the proper expression of FXYD2. Our results reveal FXYD2 as a new target of the Ret signaling pathway during normal maturation of the DRG and after sciatic nerve injury in the non-peptidergic nociceptive neurons
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