Molecular and Cellular Mechanisms of Teneurin Signaling in Synaptic Partner Matching

Abstract

SUMMARYIn developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionally conserved teneurins were the first identified transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurin’s functions is unclear. Here, we usein situproximity labeling to obtain the intracellular interactome of teneurin (Ten-m) in theDrosophilabrain. 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.HIGHLIGHTSIn situspatial proteomics reveal the first intracellular interactome of teneurinsTen-m signals via a RhoGAP and Rac1 GTPase to regulate synaptic partner matchingSingle-axon analyses reveal a stabilization-upon-contact model for partner matchingTen-m signaling promotes F-actin in axon branches contacting partner dendrites