Zcchc12-Containing Nociceptors Are Required for Noxious Heat Sensation

Abstract

DRG neurons are classified into distinct types to mediate the somatosensation with different modalities. Recently, transcriptional profilings of DRG neurons by single-cell RNA-sequencing have provided new insights into the neuron typing and functional properties. Zinc-finger CCHC domain-containing 12 (Zcchc12) was reported to be the representative marker for a subtype of galanin-positive (Gal+) DRG neurons. However, the characteristics and functions ofZcchc12+neurons are largely unknown. Here, we genetically labeledZcchc12+neurons inZcchc12-CreERT2::Ai9 mice, and verified thatZcchc12represented a new subpopulation of DRG neurons in both sexes.Zcchc12+neurons centrally innervated the superficial laminae in spinal dorsal horn, and peripherally terminated as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. In addition,Zcchc12+neurons also formed circumferential endings surrounding the hair follicles in hairy skin. Functionally,in vivocalcium imaging in DRGs revealed thatZcchc12+neurons were polymodal nociceptors and could be activated by mechanical and noxious thermal stimuli. Behavioral tests showed that selective ablation ofZcchc12+DRG neurons reduced the sensitivity to noxious heat in mice. Together, we identified a new subpopulation ofZcchc12+nociceptors essential for noxious heat sensation.SIGNIFICANCE STATEMENTZcchc12represents a new subpopulation of DRG neurons. The characteristics and functions ofZcchc12+neurons are largely unknown. Here we genetically labeledZcchc12+neurons, and showed that the fibers ofZcchc12+DRG neurons projected to superficial lamina at spinal dorsal horn, and innervated skin as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Functionally,Zcchc12+DRG neurons responded to noxious mechanical and heat stimuli. Ablation ofZcchc12+DRG neurons impaired the sensation of noxious heat in mice. Therefore, we identify a new subpopulation of DRG neurons required for noxious heat sensation.