Podcast with Peter Mombaerts on olfactory system and odorant receptor genes

How does a mouse nose with 1,200 receptor genes wire itself into a precise sensory map, and why is that map less stereotyped than we once believed? Peter Mombaerts explores the genetics and development of olfactory circuit formation.

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Peter Mombaerts describes the remarkable complexity of the mouse olfactory system, where approximately 1,200 odorant receptor genes each expressed by a distinct population of sensory neurons must organize their axonal projections into roughly 3,600 glomeruli in the olfactory bulb. Using gene targeting and molecular labeling techniques, his laboratory has spent two decades investigating how this glomerular map develops and what role the receptor proteins themselves play in axon guidance and glomerular identity.

A central theme is the surprising degree of variability in glomerular positioning. Mombaerts challenges the widely used term "stereotyped" to describe the glomerular map, demonstrating that even between the left and right bulbs of the same inbred mouse, the relative positions of identified glomeruli can be inverted. He prefers terms like "recognizable" or "reproducible," noting that the precision is insufficient to construct a definitive atlas as has been done for Drosophila. This variability has important implications for understanding the mechanisms of map formation: if the map were truly stereotyped, extremely complex molecular guidance mechanisms would be required, but acknowledging the jitter relaxes these demands considerably.

The conversation explores the genomic organization of odorant receptor genes, which Mombaerts describes as "haphazard," distributed across approximately 40 loci with the largest cluster containing around 300 genes. Expression levels vary over two orders of magnitude between different receptor types, and the one-neuron-one-receptor rule, while strongly supported, remains an asymptotic conclusion. Remarkably, replacing an odorant receptor's coding region with the beta-2 adrenergic receptor still produces neurons that form a recognizable glomerulus and respond to appropriate ligands, suggesting that the receptor protein's role in axon guidance may not be unique to olfactory receptors.

The episode also addresses the emerging recognition that odorant receptor genes are expressed outside the nose, including in kidneys where knockout of one receptor affects blood pressure regulation, hinting at broader biological roles for this gene family beyond olfaction.