Single-nucleus analysis of the adult human olfactory epithelium uncovers shared neurogenesis programs with the brain.

Neurogenesis, a critical process implicated in diverse brain disorders, is greatly diminished in the adult human brain, complicating direct investigations into its mechanistic role in disease. In the olfactory epithelium (OE), olfactory sensory neurons (OSNs) maintain homeostasis via continual neurogenesis throughout life, providing a niche to investigate neurogenesis in vivo. However, the molecular mechanisms underlying this process and its similarities to brain neurogenesis remain largely unknown. Here, we performed single-nucleus RNA-seq on specimens of human OE from 6 living adult donors, yielding high-quality transcriptomes representing 145,720 cells. Integrating with two independent OE single-cell transcriptomics datasets, different developmental stages of OSNs were identified, including neural precursor cells (globose basal cells, GBCs), as well as immature and mature OSNs. We inferred trajectories and assessed the transcriptional and regulatory dynamics of OSN development. Genes and transcription factors (TFs) involved in regulating neuronal differentiation and neurogenesis were highly expressed in GBCs and early immature OSNs, but were downregulated in mature neurons. OSNs and cortical excitatory neurons exhibited convergence during early developmental stages, including dynamically expressed genes, TFs, biological processes, and polygenic enrichment for psychiatric disorders. In addition, expression trajectory alignment between OSNs and cortical excitatory neurons (CENs) revealed that OSNs could partially track the expression dynamics of autism spectrum disorder (ASD) risk genes in CENs. Overall, cells in the neuronal lineage of the OE represent a potential proxy to study gene programs involved in neurogenesis in the human brain, providing an accessible model for investigating neurodevelopmental dysfunction in psychiatric disorders.