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The olfactory system serves a critical function as a danger detection system to trigger defense responses essential for survival. The cellular and molecular mechanisms that drive such defenses in mammals are incompletely understood. Here, we have discovered an ultrasensitive olfactory sensor for the highly poisonous bacterial metabolite hydrogen sulfide (H 2 S) in mice. An atypical class of sensory neurons in the main olfactory epithelium, the type B cells, is activated by both H 2 S and low O 2 . These two stimuli trigger, respectively, Cnga2- and Trpc2-signaling pathways, which operate in separate subcellular compartments, the cilia and the dendritic knob. This activation drives essential defensive responses: elevation of the stress hormone ACTH, stress-related self-grooming behavior, and conditioned place avoidance. Our findings identify a previously unknown signaling paradigm in mammalian olfaction and define type B cells as chemosensory neurons that integrate distinct danger inputs from the external environment with appropriate defense outputs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The mouse vomeronasal organ (VNO) has a pivotal role in chemical communication. The vomeronasal sensory neuroepithelium consists of distinct populations of vomeronasal sensory neurons (VSNs). A subset of VSNs, with cell bodies in the basal part of the basal layer, coexpress Vmn2r G-protein-coupled receptor genes with H2-Mv genes, a family of nine nonclassical class I major histocompatibility complex genes. The in vivo, physiological roles of the H2-Mv gene family remain mysterious more than a decade after the discovery of combinatorial H2-Mv gene expression in VSNs. Here, we have taken a genetic approach and have deleted the 530 kb cluster of H2-Mv genes in the mouse germline by chromosome engineering. Homozygous mutant mice (ΔH2Mv mice) are viable and fertile. There are no major anatomical defects in their VNO and accessory olfactory bulb (AOB). Their VSNs can be stimulated with chemostimuli (peptides and proteins) to the same maximum responses as VSNs of wild-type mice, but require much higher concentrations. This physiological phenotype is displayed at the single-cell level and is cell autonomous: single V2rf2-expressing VSNs, which normally coexpress H2-Mv genes, display a decreased sensitivity to a peptide ligand in ΔH2Mv mice, whereas single V2r1b-expressing VSNs, which do not coexpress H2-Mv genes, show normal sensitivity to a peptide ligand in ΔH2Mv mice. Consistent with the greatly decreased VSN sensitivity, ΔH2Mv mice display pronounced deficits in aggressive and sexual behaviors. Thus, H2-Mv genes are not absolutely essential for the generation of physiological responses, but are required for ultrasensitive chemodetection by a subset of VSNs.

In addition to their role in the immune response, peptide ligands of major histocompatibility complex (MHC) molecules function as olfactory cues for subsets of vomeronasal sensory neurons (VSNs) in the mammalian nose. How MHC peptide diversity is recognized and encoded by these cells is unclear. We found that mouse VSNs expressing the vomeronasal receptor gene V2r1b (also known as Vmn2r26) detected MHC peptides at subpicomolar concentrations and exhibited combinatorial activation with overlapping specificities. In a given cell, peptide responsiveness was broad, but highly specific; peptides differing by a single amino-acid residue could be distinguished. Cells transcribing a V2r1b locus that has been disrupted by gene targeting no longer showed such peptide responses. Our results reveal fundamental parameters governing the response to MHC peptides by VSNs. We suggest that the peptide presentation system provided by MHC molecules co-evolves with the peptide recognition systems expressed by T cells and VSNs.

The mammalian olfactory system has developed some functionality by the time of birth. There is behavioral and limited electrophysiological evidence for prenatal olfaction in various mammalian species. However, there have been no reports, in any mammalian species, of recordings from prenatal olfactory sensory neurons ( OSNs) that express a given odorant receptor ( OR) gene. Here we have performed patch-clamp recordings from mouse OSNs that express the OR gene S1 or MOR23, using the odorous ligands 2-phenylethyl alcohol or lyral, respectively. We found that, out of a combined total of 20 OSNs from embryos of these two strains at embryonic day ( E)16.5 or later, all responded to a cognate odorous ligand. By contrast, none of six OSNs responded to the ligand at E14.5 or E15.5. The kinetics of the odorant-evoked electrophysiological responses of prenatal OSNs are similar to those of postnatal OSNs. The S1 and MOR23 glomeruli in the olfactory bulb are formed postnatally, but the axon terminals of OSNs expressing these OR genes may be synaptically active in the olfactory bulb at embryonic stages. The upper limit of the acquisition of odorant responsiveness for S1 and MOR23 OSNs at E16.5 is consistent with the developmental expression patterns of components of the olfactory signaling pathway. [ABSTRACT FROM AUTHOR]

The current consensus model in mammalian olfaction is that the detection of millions of odorants requires a large number of odorant receptors (ORs) and that each OR interacts selectively with a small subset of odorants, which are typically related in structure. Here, we report the odorant response properties of an OR that deviates from this model: SR1, a mouse OR that is abundantly expressed in sensory neurons of the septal organ and also of the main olfactory epithelium. Patch-clamp recordings reveal that olfactory sensory neurons (OSNs) that express SR1 respond to many, structurally unrelated odorants, and over a wide concentration range. Most OSNs expressing a gene-targeted SR1 locus that lacks the SR1 coding sequence do not show this broad responsiveness. Gene transfer in the heterologous expression system Hana3A confirms the broad response profile of SR1. There maybe other mouse ORs with such broad response profiles. [ABSTRACT FROM AUTHOR]

The main olfactory epithelium of the mouse is a mosaic of 2000 populations of olfactory, sensory, neurons (OSNs). Each population expresses one allele of one of the 1000 intact odorant receptor (OR) genes. An OSN projects a single unbranched axon to a single glomerulus, from an array of 1600-1800 glomeruli in the main olfactory bulb. Within a glomerulus the OSN axon synapses with the dendrites of second-order neurons and interneurons. Axons of OSNs that express the same OR project to the same glomeruli--typically one glomerulus per half-bulb and thus four glomeruli per mouse. These glomeruli are located at characteristic positions within the glomerular layer of the bulb. ORs determine both the odorant response profile of the OSN and the projection of its axon to a specific glomerulus. I focus on genetic approaches to the axonal wiring problem, particularly on how ORs may function in axonal wiring. [ABSTRACT FROM AUTHOR]

Abstract: There is an overall topographic connectivity in the axonal projections of olfactory sensory neurons from the olfactory epithelium (OE) to the olfactory bulb (OB). The molecular determinants of this overall topographic OE–OB connectivity are not known. For 20 years, the intriguing expression pattern of the olfactory cell adhesion molecule (OCAM) has made it the leading candidate as determinant of overall topographic OE–OB connectivity. Here, we have generated a strain of OCAM knockout mice by gene targeting. There were no obvious alterations in the distribution of olfactory sensory neurons within the OE or in the coalescence of axons into specific glomeruli. However, the compartmental organization of dendrites and axons within the glomeruli was disrupted. Surprisingly, the mutant mice exhibited an increase in olfactory acuity; they appeared to have a better sense of smell. Thus, despite its striking expression pattern, OCAM is not essential for overall topographic OE–OB connectivity. Instead, OCAM is required for establishing or maintaining the compartmental organization and the segregation of axodendritic and dendrodendritic synapses within glomeruli. [Copyright &y& Elsevier]

The mammalian Olf1/EBF (O/E) family of repeated helix-loop-helix (rHLH) transcription factors has been implicated in olfactory system gene regulation, nervous system development and B-cell differentiation. Ebf (O/E1) mutant animals showed defects in B-cell lineage and brain regions where it is the only O/E family member expressed, but the olfactory epithelium appeared unaffected and olfactory marker expression was grossly normal in these animals. In order to further study the mammalian O/E proteins, we disrupted O/E2 and O/E3 genes in mouse and placed tau-lacZ and tau-GFP reporter genes under the control of the respective endogenous O/E promoters. Mice mutant for each of these genes display reduced viability and other gene-specific phenotypes. Interestingly, both O/E2 and O/E3 knockout mice as well as O/E2/O/E3 double heterozygous animals share a common phenotype; olfactory neurons (ORN) fail to project to dorsal olfactory bulb. We suggest that a decreased dose of O/E protein may alter expression of O/E target genes and underlie the ORN projection defect. [ABSTRACT FROM AUTHOR]

Determines whether or not V1r gene receptors are involved in the behavioral and electrophysiological responses to pheromones by deleting a cluster of V1r genes in the germ line of mice. Deficits in a subset of vomeronasal organ (VNO)-dependent behaviors that are exhibited by the mutant mice; Failure of the epithelium of the VNO of the mutant mice to respond detectably to specific pheromonal ligands.

The mouse's sense of smell is built of ∼1000 input channels. Each of these consists of a population of olfactory sensory neurons that express the same odorant receptor gene and project their axons to the same targets (glomeruli) in the olfactory bulb. A neuron must choose to express a singular receptor gene from a repertoire of ∼1000 genes, and its axon must be wired to the corresponding glomerulus, from an array of ∼1800 glomeruli. Genetic experiments have shown that the expressed odorant receptor specifies axonal choice of the innervated glomerulus, but it is not the only determinant. The mechanisms of odorant receptor gene choice and axonal wiring are central to the functional organization of the mammalian olfactory system. Although principles have emerged, our understanding of these processes is still limited. [ABSTRACT FROM AUTHOR]

Examines research on the human odorant receptor (OR) genes and pseudogenes. Details on the discovery and characterization of OR genes; Expression patterns of vertebrate OR genes; Discussion on the genomic phase.

Presents information on a study which identified seven-transmembrane proteins as odorant and chemosensory receptors among vertebrates and two invertebrates. Methodology of the study; Results and discussion on the study; Conclusions.

Summarizes studies related to the molecular biology of odorant receptors in vertebrates. Initial discovery; Organization of odor receptors in the genome; Functions.

Axonal projections from the olfactory epithelium to the olfactory bulb are organized into glomeruli according to the expressed odorant receptor. Using gene-targeted mice, we show that glomerular maturation proceeds along different time courses for two similar receptors and requires sensory input during distinct sensitive periods. During early development, some glomeruli are innervated by axons of neurons that do not express the same receptor. These heterogeneous glomeruli normally disappear with age, but they persist in adults deprived of sensory input by unilateral and permanent naris closure. Persistence may be due, in part, to prolonged survival of olfactory sensory neurons. [ABSTRACT FROM AUTHOR]