Zcchc12-Containing Nociceptors Are Required for Noxious Heat Sensation.

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 of Zcchc12(+) neurons are largely unknown. Here, we genetically labeled Zcchc12(+) neurons in Zcchc12-CreERT2::Ai9 mice, and verified that Zcchc12 represented 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 vivo calcium imaging in DRGs revealed that Zcchc12(+) neurons were polymodal nociceptors and could be activated by mechanical and noxious thermal stimuli. Behavioral tests showed that selective ablation of Zcchc12(+) DRG neurons reduced the sensitivity to noxious heat in mice. Together, we identified a new subpopulation of Zcchc12(+) nociceptors essential for noxious heat sensation.SIGNIFICANCE STATEMENTZcchc12 represents a new subpopulation of DRG neurons. The characteristics and functions of Zcchc12(+) neurons are largely unknown. Here we genetically labeled Zcchc12(+) neurons, and showed that the fibers of Zcchc12(+) 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 of Zcchc12(+) DRG neurons impaired the sensation of noxious heat in mice. Therefore, we identify a new subpopulation of DRG neurons required for noxious heat sensation.