Gene expression programs in the nose

Abstract

Sensory processing in the nose filters the external olfactory world and supports a wide variety of olfactory behaviors that are fundamental to life. Natural odor stimuli are complex mixtures of volatile chemicals that interact with an array of chemical detectors in olfactory sensory neurons that, in rodents, is built from more than 1,000 unique odorant receptors. These odorant receptors are expressed in a one receptor per neuron fashion, leading to ~1,000 different olfactory sensory neuron subtypes in the rodent nose. Since each olfactory sensory neuron subtype can be identified across individuals based upon its expression of a single odorant receptor, the nose provides a model system to query transcriptional variation and functional differences in parallel across subtypes and contexts. In this work we use single-cell genomic approaches to identify nasal targets of pathogens and to comprehensively probe the normal physiology of the nose.

We first examined the expression patterns of genes required for coronavirus cell entry in the nasal epithelium and found that these genes were only expressed in non-neuronal supportive cells in mice and humans, suggesting that infection of these supportive cells rather than sensory neurons leads to the widespread impairment of smell observed in COVID-19 patients. Second, we developed approaches to decompose transcriptional variation across olfactory sensory neurons into gene expression programs that reflect differences in either cellular activity or identities. We discovered that each of the ~1,000 olfactory sensory neuron subtypes harbors a distinct transcriptome whose content is precisely shaped by interactions between its odorant receptor and the environment. Analog changes in activity deterministically yield proportional, bidirectional, and coordinated changes in the expression of ~100 genes that adaptively tune sensory responses. In contrast, dorsoventral identities also vary across olfactory sensory neuron subtypes, but they emerge prior to olfactory receptor expression and remain constant across environmental contexts. In combination with clonal lineage tracing experiments, we integrated single-cell gene expression patterns with spatial transcriptomics datasets and find that these identity programs map smoothly onto the nasal epithelium, yielding a precise and unique spatial position for each sensory neuron subtype. Taken together, our work identifies fixed and flexible gene expression programs that independently maintain constant aspects of neuronal identities while also supporting ongoing adaptation.