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Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome 1 – 3 . How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight into how an odorant binds to a human odorant receptor. Using cryo-electron microscopy, we determined the structure of the active human odorant receptor OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant-binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor. Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate odorant receptor, providing insight into how this large family of G protein-coupled receptors enables our olfactory sense. Through the use of cryo-electron microscopy and molecular dynamics stimulations, mechanistic insight into the binding of an odorant to the human odorant receptor OR51E2 is provided.

Olfactory and taste receptors are expressed primarily in the nasal olfactory epithelium and gustatory taste bud cells, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple extra-nasal and extra-oral tissues, being implicated in diverse biological processes including sperm chemotaxis, muscle regeneration, bronchoconstriction and bronchodilatation, inflammation, appetite regulation and energy metabolism. Elucidation of the physiological roles of these ectopic receptors is revealing potential therapeutic and diagnostic applications in conditions including wounds, hair loss, asthma, obesity and cancers. This Review outlines current understanding of the diverse functions of ectopic olfactory and taste receptors and assesses their potential to be therapeutically exploited.

The olfactory system must recognize and discriminate amongst an enormous variety of chemicals in the environment. To contend with such diversity, insects have evolved a family of odorant-gated ion channels comprised of a highly conserved co-receptor (Orco) and a divergent odorant receptor (OR) that confers chemical specificity. Here, we present the single-particle cryo-electron microscopy structure of an Orco homomer from the parasitic fig wasp Apocrypta bakeri at 3.5 Å resolution, providing structural insight into this receptor family. Orco possesses a novel channel architecture, with four subunits symmetrically arranged around a central pore that diverges into four lateral conduits that open to the cytosol. The Orco tetramer has few inter-subunit interactions within the membrane and is bound together by a small cytoplasmic anchor domain. The minimal sequence conservation among ORs maps largely to the pore and anchor domain, shedding light on how the architecture of this receptor family accommodates its remarkable sequence diversity and facilitates the evolution of odour tuning. A cryo-electron microscopy structure of the insect Orco subunit, which forms ion channels with diverse olfactory receptors, reveals a tetrameric cation channel and sheds light on insect olfaction.

The genome is partitioned into topologically associated domains and genomic compartments with shared chromatin valence. This architecture is constrained by the DNA polymer, which precludes interactions between genes on different chromosomes. Here we report a marked divergence from this pattern of nuclear organization that occurs in mouse olfactory sensory neurons. Chromatin conformation capture using in situ Hi-C on fluorescence-activated cell-sorted olfactory sensory neurons and their progenitors shows that olfactory receptor gene clusters from 18 chromosomes make specific and robust interchromosomal contacts that increase with differentiation of the cells. These contacts are orchestrated by intergenic olfactory receptor enhancers, the ‘Greek islands’, which first contribute to the formation of olfactory receptor compartments and then form a multi-chromosomal super-enhancer that associates with the single active olfactory receptor gene. The Greek-island-bound transcription factor LHX2 and adaptor protein LDB1 regulate the assembly and maintenance of olfactory receptor compartments, Greek island hubs and olfactory receptor transcription, providing mechanistic insights into and functional support for the role of trans interactions in gene expression. Specific interchromosomal contacts in olfactory sensory neurons form a super-enhancer that controls the expression of a single olfactory receptor in each neuron.

The presence of active neurogenic niches in adult humans is controversial. We focused attention to the human olfactory neuroepithelium, an extracranial site supplying input to the olfactory bulbs of the brain. Using single-cell RNA sequencing analyzing 28,726 cells, we identified neural stem cell and neural progenitor cell pools and neurons. Additionally, we detailed the expression of 140 olfactory receptors. These data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans.Durante et al. report the presence of active neurogenic niches in adult humans using single-cell RNA sequencing of the human olfactory neuroepithelium. Data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans.

Female mosquitoes are major vectors of human disease and the most dangerous are those that preferentially bite humans. A ‘domestic’ form of the mosquito Aedes aegypti has evolved to specialize in biting humans and is the main worldwide vector of dengue, yellow fever, and chikungunya viruses. The domestic form coexists with an ancestral, ‘forest’ form that prefers to bite non-human animals and is found along the coast of Kenya. We collected the two forms, established laboratory colonies, and document striking divergence in preference for human versus non-human animal odour. We further show that the evolution of preference for human odour in domestic mosquitoes is tightly linked to increases in the expression and ligand-sensitivity of the odorant receptor AaegOr4 , which we found recognizes a compound present at high levels in human odour. Our results provide a rare example of a gene contributing to behavioural evolution and provide insight into how disease-vectoring mosquitoes came to specialize on humans. The mosquito Aedes aegypti includes two subspecies, one of which shows a preference for biting humans, whereas the other prefers to bite non-human animals; genetic analysis reveals that changes in the mosquito odorant receptor Or4 contribute to the behavioural difference—in human-preferring mosquitoes, Or4 is more highly expressed and more sensitive to sulcatone, a compound present at high levels in human odour. How mosquitoes got a taste for human blood A 'domestic' form of the mosquito Aedes aegypti , which is the major worldwide vector of dengue, yellow fever and chikungya viruses, has evolved from an ancestral 'forest' form. The former preferentially bites humans, the latter avoids them. Leslie Vosshall and colleagues collected the two forms where they coexist in coastal Kenya, and document striking divergence in preference for human versus animal odour. The human-preferring mosquito carries a version of the olfactory receptor Or4 that is more highly expressed, with greater ligand sensitivity and that makes the mosquito more sensitive to sulcatone, a compound found at high concentration in human odour. This finding provides a rare example of a gene linked to the evolution of behaviour in natural populations.

Mosquitoes are vectors for multiple infectious human diseases and use a variety of sensory cues (olfactory, temperature, humidity and visual) to locate a human host. A comprehensive understanding of the circuitry underlying sensory signalling in the mosquito brain is lacking. Here we used the Q-system of binary gene expression to develop transgenic lines of Anopheles gambiae in which olfactory receptor neurons expressing the odorant receptor co-receptor ( Orco ) gene are labelled with GFP. These neurons project from the antennae and maxillary palps to the antennal lobe (AL) and from the labella on the proboscis to the suboesophageal zone (SEZ), suggesting integration of olfactory and gustatory signals occurs in this brain region. We present detailed anatomical maps of olfactory innervations in the AL and the SEZ, identifying glomeruli that may respond to human body odours or carbon dioxide. Our results pave the way for anatomical and functional neurogenetic studies of sensory processing in mosquitoes. Mosquitoes use olfactory cues to locate their host. Here, Riabinina et al . use genetic labelling of olfactory receptor neurons in the malaria vector Anopheles gambiae to show that these neurons project to the antennal lobe, a known insect olfactory centre, and the subesophageal zone, a region previously linked to gustatory processing.

The evolution of animal behaviour is poorly understood 1 , 2 . Despite numerous correlations between interspecific divergence in behaviour and nervous system structure and function, demonstrations of the genetic basis of these behavioural differences remain rare 3 – 5 . Here we develop a neurogenetic model, Drosophila sechellia , a species that displays marked differences in behaviour compared to its close cousin Drosophila melanogaster 6 , 7 , which are linked to its extreme specialization on noni fruit ( Morinda citrifolia ) 8 – 16 . Using calcium imaging, we identify olfactory pathways in D. sechellia that detect volatiles emitted by the noni host. Our mutational analysis indicates roles for different olfactory receptors in long- and short-range attraction to noni, and our cross-species allele-transfer experiments demonstrate that the tuning of one of these receptors is important for species-specific host-seeking. We identify the molecular determinants of this functional change, and characterize their evolutionary origin and behavioural importance. We perform circuit tracing in the D. sechellia brain, and find that receptor adaptations are accompanied by increased sensory pooling onto interneurons as well as species-specific central projection patterns. This work reveals an accumulation of molecular, physiological and anatomical traits that are linked to behavioural divergence between species, and defines a model for investigating speciation and the evolution of the nervous system. A neurogenetic model, Drosophila sechellia —a relative of Drosophila melanogaster that has developed an extreme specialization for a single host plant—sheds light on the evolution of interspecific differences in behaviour.

Insects detect their hosts or mates primarily through olfaction, and olfactory receptors (ORs) are at the core of odorant detection. Each species has evolved a unique repertoire of ORs whose functional properties are expected to meet its ecological needs, though little is known about the molecular basis of olfaction outside Diptera. Here we report a pioneer functional analysis of a large array of ORs in a lepidopteran, the herbivorous pest Spodoptera littoralis. We demonstrate that most ORs are narrowly tuned to ubiquitous plant volatiles at low, relevant odorant titres. Our phylogenetic analysis highlights a basic conservation of function within the receptor repertoire of Lepidoptera, across the expansive evolutionary radiation of different major clades. Our study provides a reference for further studies of olfactory mechanisms in Lepidoptera, a historically crucial insect order in olfactory research.

Olfactory receptor (OR) choice provides an extreme example of allelic competition for transcriptional dominance, where every olfactory neuron stably transcribes one of approximately 2,000 or more OR alleles 1 , 2 . OR gene choice is mediated by a multichromosomal enhancer hub that activates transcription at a single OR 3 , 4 , followed by OR-translation-dependent feedback that stabilizes this choice 5 , 6 . Here, using single-cell genomics, we show formation of many competing hubs with variable enhancer composition, only one of which retains euchromatic features and transcriptional competence. Furthermore, we provide evidence that OR transcription recruits enhancers and reinforces enhancer hub activity locally, whereas OR RNA inhibits transcription of competing ORs over distance, promoting transition to transcriptional singularity. Whereas OR transcription is sufficient to break the symmetry between equipotent enhancer hubs, OR translation stabilizes transcription at the prevailing hub, indicating that there may be sequential non-coding and coding mechanisms that are implemented by OR alleles for transcriptional prevalence. We propose that coding OR mRNAs possess non-coding functions that influence nuclear architecture, enhance their own transcription and inhibit transcription from their competitors, with generalizable implications for probabilistic cell fate decisions. Messenger RNAs transcribed from olfactory-receptor genes may have non-coding functions that include recruitment of transcriptional enhancers and inhibition of potentially thousands of competing alleles to ensure stable transcription of a single allele.