Individual olfactory sensory neurons express only a single odorant receptor from a large family of genes, and this singularity is an essential feature in models of olfactory perception. We have devised a genetic strategy to examine the stability of receptor choice. We observe that immature olfactory sensory neurons that express a given odorant receptor can switch receptor expression, albeit at low frequency. Neurons that express a mutant receptor gene switch receptor transcription with significantly greater probability, suggesting that the expression of a functional odorant receptor elicits a feedback signal that terminates switching. This process of receptor gene switching assures that a neuron will ultimately express a functional receptor and that the choice of this receptor will remain stable for the life of the cell.
Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells but its function is poorly understood. Here, we show that Hdc knockout mice exhibit a markedly increased rate of colon and skin carcinogenesis. Using Hdc-EGFP BAC transgenic mice, we demonstrate that Hdc is expressed primarily in CD11b+Ly6G+ immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wildtype recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype. In addition, IMCs from Hdc knockout mice promote the growth of cancer xenografts and colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibits myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of xenografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation, and CD11b+Ly6G+ IMCs in early cancer development.
SUMMARY
The recognition of odors is accomplished in the sensory epithelium where individual olfactory neurons express only one of 1,300 odorant receptor genes. Neurons expressing a given receptor project to two spatially invariant glomeruli in the olfactory bulb such that each odor elicits a distinct and sparse pattern of glomerular activity. We have altered the neural representation of odors in the brain by generating a mouse with a “monoclonal nose” in which greater than 95% of the sensory neurons express a single odorant receptor, M71. As a consequence, the frequency of sensory neurons expressing endogenous receptor genes is reduced twenty-fold. We observe that these mice can smell but odor discrimination and performance in associative olfactory learning tasks are impaired. However, these mice cannot detect the M71 ligand acetophenone despite the observation that virtually all sensory neurons and glomeruli are activated by this odor. The M71 transgenic mice readily detect other odors in the presence of acetophenone. These observations have implications for how receptor activation in the periphery is represented in the brain and how these representations encode odors.
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