Molecular and cellular mechanisms of teneurin signaling in synaptic partner matching

In developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionarily conserved teneurins are transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurins’ functions is unclear. Here, we use in situ proximity labeling to obtain the intracellular interactome of a teneurin (Ten-m) in the Drosophila brain. Genetic interaction studies using quantitative partner matching assays in both olfactory receptor neurons (ORNs) and projection neurons (PNs) reveal a common pathway: Ten-m binds to and negatively regulates a RhoGAP, thus activating the Rac1 small GTPases to promote synaptic partner matching. Developmental analyses with single-axon resolution identify the cellular mechanism of synaptic partner matching: Ten-m signaling promotes local F-actin levels and stabilizes ORN axon branches that contact partner PN dendrites. Combining spatial proteomics and high-resolution phenotypic analyses, this study advanced our understanding of both cellular and molecular mechanisms of synaptic partner matching. [Display omitted] •In situ spatial proteomics reveals the intracellular interactome of a teneurin•Ten-m signals via a RhoGAP and Rac1 GTPase to regulate synaptic partner matching•Single-axon analyses reveal a stabilization-upon-contact model for partner matching•Ten-m signaling promotes F-actin in axon branches contacting partner dendrites Synaptic partner matching in the fly olfactory circuit is achieved by selectively stabilizing axon branches by partner dendrites. Synaptic partner matching molecule Ten-m regulates this process by binding to and negatively regulating a RhoGAP, which in turn activates the Rac1 small GTPase to promote actin polymerization.