Axonal wiring

We have developed genetic approaches in mice to visualize or manipulate a population of OSNs that express the same OR, using gene targeting in embryonic stem cells. A typical design is the co-expression of an axonal marker such as taulacZ or tauGFP with an OR gene, which is made possible at the translational level by virtue of an internal ribosome entry site. Gene-targeted mutations in the OR coding sequence, such as its replacement by the coding sequence of another OR, have collectively demonstrated that the OR is instrumental in axonal coalescence itself, and in determining the approximate site in the glomerular layer of the olfactory bulb where axonal coalescence occurs. An extensive series of gene-targeted mice led us to propose a model of homophilic interactions between ORs or OR-containing membrane complexes as a fundamental mechanism of OR-dependent coalescence of axons into glomeruli. We have recently found that there are two OSN types, which express either class I or class II ORs, and that these OSN types are determinants of axonal wiring, operating at a level higher than the ORs.

Vomeronasal receptors and pheromones

The vomeronasal organ (VNO) in the nasal cavity of the mouse is specialized in the detection of pheromones, but it is responsive to other chemosensory stimuli as well, and conversely, the main olfactory epithelium can also detect compounds with pheromonal effects. The vomeronasal sensory neurons (VSNs) of the VNO express G-protein coupled receptors of two other large gene families, which are unrelated to ORs: the V1Rs and V2Rs. With our genetic approach we have demonstrated that axons of VSNs that express a given V1R or V2R coalesce into multiple, smaller glomeruli in the accessory olfactory bulb. We have shown that a given VR gene is expressed from one allele in an individual VSN. By generating mice that lack a cluster of 16 V1R genes via chromosome engineering, we have provided in vivo evidence for a role of V1Rs in pheromone behaviors. We have discovered a family of nine non-classical class I Major histocompatibility genes, H2-Mv genes. These genes are expressed only in the VNO, specifically in VSNs that express V2R genes, and in particular combinatorial patterns. Their function and regulation remain elusive.