An epigenetic trap stabilizes singular olfactory receptor expression.

The molecular mechanisms regulating olfactory receptor (OR) expression in the mammalian nose are not yet understood. Here, we identify the transient expression of histone demethylase LSD1 and the OR-dependent expression of adenylyl cyclase 3 (Adcy3) as requirements for initiation and stabilization of OR expression. As a transcriptional coactivator, LSD1 is necessary for desilencing and initiating OR transcription, but as a transcriptional corepressor, it is incompatible with maintenance of OR expression, and its downregulation is imperative for stable OR choice. Adcy3, a sensor of OR expression and a transmitter of an OR-elicited feedback, mediates the downregulation of LSD1 and promotes the differentiation of olfactory sensory neurons (OSNs). This novel, three-node signaling cascade locks the epigenetic state of the chosen OR, stabilizes its singular expression, and prevents the transcriptional activation of additional OR alleles for the life of the neuron.

Neurons expressing trace amine-associated receptors project to discrete glomeruli and constitute an olfactory subsystem.

Some chemoreceptors of the trace amine-associated receptor (TAAR) family detect innately aversive odors and are proposed to activate hardwired olfactory circuits. However, the wiring of TAAR neurons, the regulatory mechanisms of Taar gene choice, and the subcellular localization of TAAR proteins remain unknown. Here, we reveal similarities between neurons expressing TAARs and odorant receptors (ORs), but also unexpected differences. Like ORs, TAARs seem to be monoallelically expressed and localized both in cilia, the site of odor detection, and in axons, where they may participate in guidance. TAAR neurons project to discrete glomeruli predominantly localized to a confined bulb region. Taar expression involves different regulatory logic than OR expression, as neurons choosing a Taar5 knockout allele frequently express a second Taar without silencing the deleted allele. Moreover, the epigenetic signature of OR gene choice is absent from Taar genes. The unique molecular and anatomical features of the TAAR neurons suggest that they constitute a distinct olfactory subsystem.

A critical period defined by axon-targeting mechanisms in the murine olfactory bulb.

The olfactory system remains plastic throughout life because of continuous neurogenesis of sensory neurons in the nose and inhibitory interneurons in the olfactory bulb. Here, we reveal that transgenic expression of an odorant receptor has non-cell autonomous effects on axons expressing this receptor from the endogenous gene. Perinatal expression of transgenic odorant receptor causes rerouting of like axons to new glomeruli, whereas expression after the sensory map is established does not lead to rerouting. Further, chemical ablation of the map after rerouting does not restore the normal map, even when the transgenic receptor is no longer expressed. Our results reveal that glomeruli are designated as targets for sensory neurons expressing specific odorant receptors during a critical period in the formation of the olfactory sensory map.