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 (snRNA-seq from the human OE of 6 living adult donors, yielding 145,720 high-quality transcriptomics. Integrating with an independent OE dataset from 4 adults, 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 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, biological processes, transcription factors, as well as polygenic enrichment for psychiatric disorders. In addition, highly matched expression dynamics of autism risk genes between OSNs and cortical excitatory neurons further validated their convergence. Overall, OSNs cells in the olfactory neuroepithelium 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.