Combinatorial codes of presynaptic organizer neurexins orchestrate precise olfactory axon targeting

Precise neural wiring is essential for the formation of complex neural circuitry within the mammalian brain, particularly in the olfactory system. While trans-interactions between synaptic membrane proteins have emerged as crucial elements in orchestrating the elaborate assembly of neural circuitry, identifying which specific synaptic surface proteins are involved in the wiring processes has remained elusive. Here, we uncover neurexins, the indispensable presynaptic receptors crucial neurotransmission, as novel wiring players using unbiased approaches based on single-cell transcriptomes of olfactory sensory neurons (OSNs). The distinctive expression of neurexin isoforms in OSNs synergistically cooperates the regulation of axon innervation, guiding OSNs to their designated glomeruli, in collaboration with their postsynaptic partners which display unique patterns of expression in mitral and tufted (M/T) cells. Our findings suggest a novel mechanism underpinning the precise assembly of the olfactory circuitry, facilitated by the trans-interaction between neurexins and their partnering elements. Beyond advancing our understanding of wiring processes in the olfactory system, this study holds the promise of unveiling the intricacies that govern higher brain structure and function. Overall design: 5' scRNAseq was performed with olfactory epithelial cells isolated from wild-type mice