Olfactory System Proteins

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 Olfactory System Proteins Background

Olfaction system plays a critical role for survival and reproduction in many animal species. Odorant molecules in the environment are sensed by olfactory sensory neurons (OSN) located in the nasal cavity. Each olfactory sensory neuron has a single dendrite terminating in olfactory cilia, where odorant receptors (OR) and the signaling cascade are located, that extend into the lumen of the nasal cavity. Odorant evoked neuronal activities are transmitted through OSN axons to the olfactory bulb projection neurons. In vertebrates, odorant induced signal is mediated by G-protein-coupled receptors, which are encoded by a family of ~1000 odorant receptor (OR) genes in mouse. Each mouse OSN is likely to express only one member from this OR repertoire. Whereas a given OR is expressed by neurons scattered in broad zones of the olfactory epithelium (OE), axons from OSNs that express the same OR converge onto defined a glomerulus in the olfactory bulb (OB).


Structure of olfactory epithelium

The olfactory epithelium (OE) of vertebrates is made up of three main cell types: OSNs, basal cells and supporting non-neuronal cells. The neural stem cells of the basal layer undergo asymmetric division to produce neuronal precursor cells. The neuronal precursor cells divide symmetrically to generate two undifferentiated immature neurons. As the immature neurons start to differentiate, they migrate away from the basal layer of the epithelium. Thus, newly generated cells are distributed close to the basal layer, while the older neurons are closer to the surface of the OE. At least three stages of differentiation can be distinguished with different antibody markers. Basal cells can be identified with antibodies against keratin, differentiated immature neurons with antibodies against GAP43 and mature OSNs with antibodies against olfactory marker protein.

In vertebrate olfactory epithelium, OSNs turn over constantly. Particularly after environmental insult, large numbers of OSNs undergo apoptosis. Globos basal cells are stimulated to divide and generate OSNs to replace the lost ones. The constant replacement of OSNs provides an opportunity to study the molecular regulations of neurogenesis. OSNs mature from GAP43 expressing immature neurons into OMP position mature neurons. OSNs express one OR out of the repertoire of ~1000 genes. The selection of OR often happens at the stage of neuronal progenitors. OSNs expressing the same OR are distributed through of the olfactory epithelium, albeit restricted within roughly defined zones. There are four classical zones in the nasal epithelium. The general distributions of these 4 zones are displayed as diagonal stripes from rostro-ventral to caudal-dorsal. Some evidence suggests that there are corresponding zones in the olfactory bulb where the olfactory sensory axons target.

OSNs are continuously replaced throughout the animal’s life. Despite the presence of a thousand target choices in the OB, olfactory axons from the replaced neurons are able to re-innervate their corresponding glomerulus in the olfactory bulb. Therefore, olfactory axon projections provide an excellent model to study molecular mechanisms for the formation and maintenance of functional neuronal connections.


OSNs axonal convergence on olfactory bulb

OSNs expressing the same ORs terminate their axons in the same loci in the olfactory bulb. The guiding mechanism of OSN axons is still an outstanding question. Several lines of evidence support that the OR itself is the axon guidance molecule for OSN axon convergence. OSN express one OR gene and maintain its expression. When this OR gene is knocked out, OSNs select another OR gene to express. This phenomenon prevented using traditional gene knockout strategy to investigate the role of OR in olfactory axon guidance. It is, however, possible to swap OR genes and examine whether OR converging sites are swapped as well. Pioneered by Mombaert, OR expressing axons are visualized by a simultaneous expression of tauGFP by knockin OR-IRES-tauGFP to replace the OR. Mombaerts et al. developed a genetic approach to visualize axons from olfactory sensory neurons expressing a particular receptor axons converge on only two topographically fixed glomeruli of the OB. They also analyzed whether odorant receptors are involved in axonal guidance by a receptor swap experiment. The coding region of an odorant receptor gene P2 was replaced by that of another receptor gene M12. This experiment yielded the unexpected result that axons of M12-expressing P2 neurons converged onto glomeruli distinct from either the wild-type P2 or M12 glomeruli, but close to the normal P2 glomeruli, suggesting that odorant receptors play an instructive role but cannot be the sole determinant in the axon guidance mechanism.

Several axon guidance molecules are expressed in the olfactory system. Slit receptor, Robo-2, is expressed in OSNs in a high dorsomedial to low ventrolateral gradient across the OE and that Slit-1 and Slit-3 are expressed in the ventral region of the OB. Furthermore, Slit-1 and Robo-2 are essential for dorso-ventral segregation of OSN axons within the OB. Another molecule, Sema3A is also widely expressed in the developing rat olfactory system in which its expression at the periphery of the telencephalic vesicle may prevent penetration of initial olfactory fibers. Therefore, in mice lacking Sema3A, NPN-1+ axons are misrouted throughout the embryonic nerve layer and terminate inappropriately in ventral glomeruli of neonatal mutant mice.

In addition, OSN axons express a variety of other cell adhesion molecules, including L1, TAG-1, Kirrel2/3 and BIG-2. Coordination between olfactory receptor and expression of cell adhesion molecules is necessary for glomerular convergence of axons from sensory neurons expressing the same type of OR. A further study of cell adhesion molecules expression by specific subsets of primary olfactory axons will help to understand molecular mechanisms underlying olfactory axon guidance.