AbstractNociceptive and pruriceptive neurons in the dorsal root ganglia (DRG) convey sensations of pain and itch to the spinal cord, respectively. One subtype of mature DRG neurons, marked by Somatostatin (Sst) expression, is responsible for sensing mediators of acute itch and atopic dermatitis, including the cytokine IL-31. How itch-sensitive (pruriceptive) neurons are specified is unclear. Here we show that Tmem184b, a gene with roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors, including those for IL-31, Leukotriene C4, and Histamine. Mice lacking Tmem184b fail to respond to IL-31, but maintain normal responses to pain and mechanical force, indicating a specific behavioral defect in pruriception. Lineage-tracing studies using Sst-driven Cre recombinase show a loss of pruriceptive neurons in Tmem184b-mutant mice, suggesting a defect in neuron subtype specification. We identify an early failure of proper Wnt-dependent transcriptional signatures and signaling components in Tmem184b mutant mice that can explain the improper DRG neuronal subtype specification. Lentiviral re-expression of Tmem184b in mutant embryonic neurons restores Wnt signatures, whereas re-expression of Tmem184b in adult DRG fails to restore itch responses. Together, these data demonstrate that Tmem184b promotes adult somatosensation through developmental Wnt signaling and specification of pruriceptive neurons. Our data illuminate a new key regulatory step in the processes controlling the establishment of diversity in the somatosensory system.
Neuronal subtype specification in the cerebellum and dorsal hindbrain
