A subpopulation of itch‐sensing neurons marked by Ret and somatostatin expression

Abstract

Itch, the unpleasant sensation that elicits a desire to scratch, is mediated by specific subtypes of cutaneous sensory neuron. Here, we identify a subpopulation of itch-sensing neurons based on their expression of the receptor tyrosine kinase Ret. We apply flow cytometry to isolate Ret-positive neurons from dorsal root ganglia and detected a distinct population marked by low levels of Ret and absence of isolectin B4 binding. We determine the transcriptional profile of these neurons and demonstrate that they express neuropeptides such as somatostatin (Sst), the NGF receptor TrkA, and multiple transcripts associated with itch. We validate the selective expression of Sst using an Sst-Cre driver line and ablated these neurons by generating mice in which the diphtheria toxin receptor is conditionally expressed from the sensory neuron-specific Avil locus. Sst-Cre::Avil iDTR mice display normal nociceptive responses to thermal and mechanical stimuli. However, scratching behavior evoked by interleukin-31 (IL-31) or agonist at the 5HT 1F receptor is significantly reduced. Our data provide a molecular signature for a subpopulation of neurons activated by multiple pruritogens.

Mast cell tetrahydrobiopterin contributes to itch in mice

“…The expression pattern of specific calcium channels or receptors in BH4 responsive vs non‐responsive neurons may help to elucidate in the future for example by single cell RNA analyses, why pruriception was particularly sensitive to GCH1/BH4. Alternatively, reporter mouse lines like Runx1‐GFP or Ret‐GFP may help to identify BH4 susceptible sensory neuron subtypes.…”

HESC-derived sensory neurons reveal an unexpected role for PIEZO2 in nociceptor mechanotransduction

“…The receptor tyrosine kinase RET is robustly expressed in both murine and human DRGs and associated with different classes of sensory neurons. In rodents RET is expressed in a graded fashion in different subsets of nociceptors, itch-detecting neurons and LTMRs (Stantcheva et al, 2016) but largely excluded from TRKA-positive neurons (Franck et al, 2011). However, in human neurons, RET is differently distributed with nearly double the fraction of mature human nociceptors co-expressing TRKA and RET (mouse: 23,2 +/-1,8 % vs. human: 45,9 +/-0,7 %, Rostock et al, 2018).…”

Interventions in the B‐type natriuretic peptide signalling pathway as a means of controlling chronic itch

“…NP2 neurons are characterized by the expression of MrgprA3 and MrgprC11 which also transmit chemical‐induced itch and mediate chloroquine‐ and histamine‐associated acute itch, but not related to pain sensitivity. NP3 neurons are Nppb + neurons, and these neurons express the IL‐31 receptor α (IL‐31Rα) and oncostatin M receptors, as well as CysLT2 receptors (Cysltr2), histamine H 1 receptors (HRH1), and 5‐HT 1F receptors (Htr1f) to transduce Il‐31‐, LTD 4 ‐, histamine‐, and 5‐HT‐mediated chronic allergic itch and inflammation (Abdelalim, Bellier, & Tooyama, ; Nguyen, Wu, Bonilla, von Buchholtz, & Ryba, ; Stantcheva et al, ; Usoskin et al, ; Table ). Interestingly, MrgprA3 is not detected in NP3 Nppb + neurons though both NP2 and 3 neurons are partially overlapping populations and express HRH1 as well as IL‐33 receptors.…”

“…Nppb + NP3 neurons innervate the border area between dermis and epidermis in both hairy and glabrous skin (Stantcheva et al, ), and NPRA and NPRB are expressed in both epidermis and dermis (Meng et al, ). In the periphery, somatostatin is exclusively expressed in Nppb + neurons (Table ).…”