Supplemental Digital Content is Available in the Text.Transmembrane protein 184B is necessary for the proper function of itch-sensitive sensory neurons involved in eczema through the control of Wnt pathway gene expression during development.

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Nociceptive and pruriceptive neurons in the dorsal root ganglia (DRG) convey sensations of pain and itch to the spinal cord, respectively. A sub-population of these neurons, marked by Somatostatin (Sst) expression, is responsible for sensing IL-31, a mediator of acute itch, atopic dermatitis, and asthma. Here we show that Tmem184b, a gene with known roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors such as 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, suggesting a specific defect in pruriception. Lineage-tracing studies using Sst-driven Cre recombinase show a loss of pruriceptive neurons in Tmem184b-mutant mice, indicating a defect in neuron subtype specification. Accordingly, Wnt-dependent transcriptional signatures and signaling components, which are essential for neuronal subtype specification during development, are markedly reduced in Tmem184b-mutant embryonic DRG. Lentiviral reexpression of Tmem184b in mutant embryonic neurons restores Wnt signatures, whereas reexpression 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.

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