Molecular and Cellular Mechanisms of Teneurin Signaling in Synaptic Partner Matching

Xu, C.; Li, Z.; Lyu, C.; Hu, Y.; McLaughlin, C.; Wong, K. K. L.; Xie, Q.; Luginbuhl, D. J.; Li, H.; Udeshi, N.; Svinkina, T.; Mani, D. R.; Carr, S. A.; Han, S.; Li, T.; Li, Y.; Guajardo, R.; Ting, A. Y.; Li, J.; Luo, L.

doi:10.1101/2024.02.23.581689

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bioRxiv · 10.1101/2024.02.23.581689

Molecular and Cellular Mechanisms of Teneurin Signaling in Synaptic Partner Matching

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Abstract

In 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 teneurins functions is unclear. Here, we use in situ proximity labeling to obtain the intracellular interactome of 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. HIGHLIGHTSO_LIIn situ spatial proteomics reveal the first intracellular interactome of teneurins C_LIO_LITen-m signals via a RhoGAP and Rac1 GTPase to regulate synaptic partner matching C_LIO_LISingle-axon analyses reveal a stabilization-upon-contact model for partner matching C_LIO_LITen-m signaling promotes F-actin in axon branches contacting partner dendrites C_LI

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Xu, C., Li, Z., Lyu, C., Hu, Y., McLaughlin, C., Wong, K. K. L., Xie, Q., Luginbuhl, D. J., Li, H., Udeshi, N., Svinkina, T., Mani, D. R., Carr, S. A., Han, S., Li, T., Li, Y., Guajardo, R., Ting, A. Y., Li, J., Luo, L.. 2024-02-23. Molecular and Cellular Mechanisms of Teneurin Signaling in Synaptic Partner Matching. https://doi.org/10.1101/2024.02.23.581689

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