Single-cell long-read profiling of olfactory sensory neuron differentiation and diversity

Olfactory sensory neurons comprise a population of highly heterogeneous subtypes. One important mechanism contributing to neuronal diversity is post-transcriptional regulation, in which isoform heterogeneity is an important component. Comprehensive profiling of transcript isoforms in olfactory sensory neurons is therefore essential for understanding the molecular mechanisms underlying their diversity. By integrating single-cell long-read sequencing with conventional 3’ RNA sequencing, we demonstrated that these neurons contain extensive isoform diversity. We identified widespread UTR remodeling and isoform switching associated with developmental stage and spatial projection pattern, providing compelling evidence for the crucial regulatory mechanism underlying OSN diversity. Furthermore, we observed co-expression of multiple isoforms from the same olfactory receptor gene within individual olfactory sensory neurons, including some predicted to encode complete transmembrane domains. Together, these data provide a resource and framework for studying how specific isoforms contribute to olfactory sensory neuron identity, axon targeting, and the maintenance of singular olfactory receptor expression. Single-cell long-read transcriptomics of mouse olfactory sensory neurons revealed isoform remodeling linked to neuronal maturation and spatial projection, alongside unexpected co-expression of multiple olfactory receptor isoforms.