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.

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.

In Alzheimer’s Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type and Tmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adult Tmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and function but may not be causal for AD and related dementias.