The functional relevance of olfactory marker protein in the vertebrate olfactory system: a never-ending story

Abstract

Olfactory marker protein (OMP) was first described as a protein expressed in olfactory receptor neurons (ORNs) in the nasal cavity. In particular, OMP, a small cytoplasmic protein, marks mature ORNs and is also expressed in the neurons of other nasal chemosensory systems: the vomeronasal organ, the septal organ of Masera, and the Grueneberg ganglion. While its expression pattern was more easily established, OMP's function remained relatively vague. To date, most of the work to understand OMP's role has been done using mice lacking OMP. This mostly phenomenological work has shown that OMP is involved in sharpening the odorant response profile and in quickening odorant response kinetics of ORNs and that it contributes to targeting of ORN axons to the olfactory bulb to refine the glomerular response map. Increasing evidence shows that OMP acts at the early stages of olfactory transduction by modulating the kinetics of cAMP, the second messenger of olfactory transduction. However, how this occurs at a mechanistic level is not understood, and it might also not be the only mechanism underlying all the changes observed in mice lacking OMP. Recently, OMP has been detected outside the nose, including the brain and other organs. Although no obvious logic has become apparent regarding the underlying commonality between nasal and extranasal expression of OMP, a broader approach to diverse cellular systems might help unravel OMP's functions and mechanisms of action inside and outside the nose.

Keywords: Olfactory bulb; Olfactory marker protein; Olfactory receptor neurons; Signal transduction.

Fig. 1. The olfactory epithelium and olfactory transduction

a: Schematic representation of the olfactory epithelium (OE). The OE is a pseudostratified epithelium consisting of several cell types, both neuronal (mature and immature ORNs) and nonneuronal. Mature ORNs are ciliated bipolar neurons extending an apical dendrite to the surface of the epithelium and a basal axon to the olfactory bulb. Nonneuronal cells in the OE include sustentacular cells (columnar supporting cells with apical microvilli), microvillar cells (a diverse population of pear-shaped cells extending an apical process with microvilli into the nasal cavity), globose basal cells (progenitors of ORNs) and horizontal basal cells (attached to the basal lamina and mitotically inactive in the uninjured OE). The OE also has Bowman’s glands (ducts projecting through the OE that release mucus). Note that the olfactory cilium and dendritic knob of ORNs are represented again in (b) and (c) respectively to highlight the olfactory transduction events related to OMP occurring at each location. b: Schematic representation of the olfactory transduction cascade occurring within the cilium of an ORN, and suggested roles of olfactory marker protein (OMP). OR, olfactory receptor; Gα_olf, β, and γ, subunits of the olfactory G protein; AC3, adenylyl cyclase 3; CNG, cyclic nucleotide-gated channel; Ano2, Ca²⁺-activated Cl⁻ channel anoctamin 2; NCKX4, K⁺-dependent Na⁺/Ca²⁺ exchanger 4; PDE1C, phosphodiesterase 1C. OMP is hypothesized to act upstream of the production of cAMP. Dashed arrows indicate the speculative effect of OMP on various elements of the olfactory transduction cascade. The OMP structure presented in this figure is a β -clamshell formed by two β sheets based on the work by Smith et al. (2002). c: Schematic representation of the hypothesized role of OMP in the dendritic knob of ORNs. An OMP dimer forms a complex with brain-expressed X-linked protein 1 (Bex1) that binds to the plasma membrane and can interact with Ca²⁺/calmodulin (CaM) and an Na⁺/Ca²⁺ exchanger (NCX). Images created with Biorender.

Fig. 2. Odorant-induced responses in wild-type and OMP-knockout mice

a: EOG recordings showing that the absence of OMP causes slower kinetics of the olfactory response, here in response to amyl acetate. EOG traces were normalized to 100% to aid comparison of the response time course and recorded from control mice (OMP^+/+), OMP-null mice (OMP^−/−), and OMP^−/− mice rescued with OMP adenoviral infection (using CMV-OMP-IRES-EGFPAdV) at day 1 postinfection (Short RES OMP^−/−) and at day 3 postinfection (RES OMP^−/−). Gray traces represent the actual EOG recordings; black curves are EOG recordings fitted with double exponential functions. Figure adapted from Ivic L et al. (2000) with permission from Nature Neuroscience. b & b’: Suction pipette recordings showing that the absence of OMP causes slower kinetics of the olfactory transduction current in single ORNs. Both traces are recorded in response to a 2-s stimulation with cineole (100 μM). b is from a control mouse (OMP^+/+). b’ is from an OMP-knockout mouse (OMP^−/−). Figure adapted from Reisert et al. (2007), with permission from the Journal of Physiology.

Fig. 3. Organization of the olfactory bulb in the presence and absence of OMP

a: Representation of a sagittal section of a mouse head. From the olfactory epithelium (OE), ORN axons pass through the cribriform plate and terminate in the glomeruli in the olfactory bulb (OB). b: Terminals of ORNs expressing the same OR converge to the same isofunctional glomeruli (shown as blue, green, or red), organized in a mirroring pattern on the medial and lateral surface of each OB hemisphere. Compared to WT and OMP^+/− mice (left), the OB of OMP-KO mice (right) is characterized by a high frequency of heterogeneous glomeruli, showing functional microdomains, each representing the terminals of ORNs expressing different ORs. GL, glomerular layer; EPL, external plexiform layer; MCL, mitral cell layer; IPL, internal plexiform layer; GCL, granule cell layer. Image created with Biorender.

Fig. 4. Glomerular macro-organization in OMP-KO mice is not altered

a: Left, Widefield view of the resting spH fluorescence in the dorsal OB surface of an OMP^−/− mouse. Scale bar, 500 μm. b: Quantification of the number of glomeruli in a central coronal section of the OB in OMP^+/− and OMP^−/− mice. n.s., not statistically significant. c & c’: Glomerular area in a central coronal section of the OB for OMP^+/− (c) and OMP^−/− (c’) mice, showing no significant difference overall. Modified from Albeanu et al. (2018), with permission from Nature Communications.

Fig. 5. OMP-KO mice show altered glomerular responses to odorants

a: Resting light images of the dorsal surface of the OB in OMP^+/− (top) and OMP^−/− (bottom) mice: response maps evoked by three different concentrations of butyl acetate (BA). Levels of glomerular activation are represented in false color (see bar in the bottom). OMP-KO mice show an overall higher number of glomeruli activated by BA at each concentration. However, there was no significant difference in maximal responses evoked at each concentration between the two mouse lines. From Kass et al. (2013a), with permission from PLoS ONE. b and c: Number of odorants able to activate a single glomerulus (b & c) and number of glomeruli responding to a single odorant (b’ & c’) in OMP^+/− (b & b’) and OMP^−/− (c & c’) mice. In OMP-KO mice, given glomeruli respond to an increased number of odorants (c, OMP^−/− 9.7 ± 0.6; OMP^+/− 8.5± 0.5) and the number of glomeruli activated by a single odorant is almost doubled (c’, OMP^−/− 16.2 ± 0.6; OMP+/− 8.2 ± 0.5). Mean ± SEM, Kolmogorov-Smirnov test). Modified from Albeanu et al. (2018), with permission from Nature Communications.