Olfactory Sensory Neuron Diversity Beyond OR Genes in mice [scRNAseq]

How functional cellular heterogeneities are regulated is fundamental for understanding the molecular basis of complex organs. Olfactory sensory neurons (OSNs) are an ideal model to investigate the regulation of cellular heterogeneity. The “one-neuron-one-receptor” organization and topographical mapping ensure the detection and precise translation of odor signals to the central neural system. Besides the diversity of OR genes and other molecular guiding axon sorting processes, single-cell transcriptome analysis revealed an OSN subpopulation, defined by Cd36, a lipid receptor gene. The function study exhibited lipid odor identification was impaired in Cd36-deficient mice. In this study, we systematically depicted the transcriptome diversity, spatial distribution, and specific functions of Cd36+ OSNs in the mouse olfactory epithelium. The specific molecular features of Cd36+ OSN we revealed implemented the programmed cellular diversity may be driven by their olfaction function. Furthermore, with the integrative analysis of single-cell transcriptome and epigenome profiles, we revealed the cis and trans regulatory signatures in Cd36+ OSN and identified Tshz1 and Mef2 as the key regulators that may directly regulate and promote the expression of Cd36 and drive the cellular diversity of OSNs. Especially, we demonstrated that Tshz1 is expressed coordinately with the choices of ORs, earlier than the expression of Cd36, which indicates it may act as a pioneer factor that instructs the lineage-specific expression of Cd36 and other genes, eventually leading to the cellular diversity of Cd36+ OSN. Our results provide novel knowledge on the regulation mechanism of cellular diversity of complex organs.