In the vertebrate nervous system, sensory information is spatially encoded in the brain, forming topographic maps that are fundamental for cognition and higher-order processing of sensory information. In the mouse olfactory system, the odor information is detected by ~1,000 types of odorant receptors (ORs). Each olfactory sensory neuron (OSN) expresses only one type of OR gene in a mono-allelic manner. OSNs expressing a given type of OR converge their axons to a specific set of glomeruli in the olfactory bulb. As a result, the odor information is topographically represented in the olfactory bulb.

It has been known that the projection sites of OSN axons are determined by the OR proteins. To understand the mechanisms of OR-instructed axonal projection, we studied the role of OR-derived signaling. We found that the OR-specific axonal projection sites are determined by quantitative levels of OR-derived cAMP signals. The cAMP in tern regulates the transcriptional levels of an axon guidance receptor, Neuropilin-1, and thereby determine the axonal projection sites along the anterior-posterior axis of the olfactory bulb.

We next asked how the topography of the map is determined according to the expression levels of Neuropilin-1. It is generally thought that the topography of the map is determined by graded positional cues that are expressed by the target. However, the olfactory map topography was established even without the olfactory bulb, indicating that the axon-axon interaction contributes to the map formation. Neuropilin-1 and its repulsive ligand, Semaphorin-3A, were found to be expressed in a complementary manner in the olfactory epithelium. Genetic manipulation of Neuropilin-1 and Semaphorin-3A in OSNs affected the pre-target axon sorting as well as the olfactory map topography. Thus, pre-target axon sorting plays an important role in establishing the topographic order based on the relative levels of guidance molecules expressed by axons.

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