oa Variegated Gene Activation and Stochastic Odorant Receptor Choice

Each olfactory sensory neuron in the mammalian nose selects just a single member of the large odorant receptor (OR) gene family. The core processes regulating OR selection may involve mechanisms that limit initial OR transcription and once a single OR is chosen, repress subsequent activations. We have used a genetic strategy to monitor the transcriptional permissiveness of the OR gene P2 by inserting an exogenous promoter, the tetracycline-dependent transactivator responsive promoter (teto), into its start site through homologous recombination. We observe that the OR locus limits the expression of the teto: repressing it outside of the wild type P2 zone while allowing sporadic activation from within its zone. Staged conditional expression experiments reveal that the receptor locus becomes fully repressed over time and that this repression does not require the receptor's open reading frame. Further, the exogenous promoter is inhibited by an OR transgene that similarly suppresses the endogenous receptor repertoire. Neurons in which both P2 alleles bear the teto-modified insertion show predominantly monoallelic expression, despite the genetic potential to express both. Finally, we observe that OR genes are expressed from the edge of pericentromeric heterochromatin. These data support a model of initiation of OR choice limited by non-permissive OR chromatin and maintained by repression of the non-selected OR genes.