Two new studies provide evidence that the monoallelic expression pattern of olfactory receptors (ORs) in mammals is regulated by a negative feedback mechanism.

The exquisite sensitivity of the mammalian olfactory system depends on functionally distinct neuronal populations that project to precisely defined glomeruli in the olfactory bulb (see figure). Establishment of these discrete populations is a function of the 'one neuron–one receptor' rule. This rule describes how each olfactory neuron expresses only one allele of one OR gene from the more than 1,000 in the mouse genome. In an effort to enhance our understanding of how this process is regulated, two research groups tested the hypothesis that the product of an expressed OR gene prevents activation of its counterparts.

Sakano and colleagues used transgenic constructs in yeast artificial chromosomes to manipulate expression of the MOR28 gene in mice. Transformation of mice with enhanced green fluorescent protein (EGFP)-tagged MOR28 from which the entire coding sequence had been deleted resulted in co-expression of EGFP and endogenous MOR28 in many cells. Other EGFP-positive neurons of the olfactory epithelium expressed different endogenous OR genes, indicating that a product of the MOR28 coding sequence is required to prevent the expression of other ORs.

Lewcock and Reed extended these findings by showing that it is the protein product of OR genes that activates the negative regulatory loop. To distinguish between possible transcriptional and translational activation of inhibition, the authors used an OR-promoter-driven transgene in which the coding sequence was present but untranslatable. The presence of this transgene did not prevent the expression of other OR alleles — strong evidence that it is OR protein rather than messenger RNA that directs the selective expression of a single OR allele.

Sakano et al. also identified a cis-acting regulatory element upstream of the MOR28 gene cluster that is necessary for gene expression. These authors suggest a model in which a transcription-activating complex is formed in this regulatory region. This complex would then interact with the promoter of just one gene in the cluster, expression of which would feed back to prevent the induction of other OR genes.