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Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice

Abstract

Synapse assembly requires trans-synaptic signals between the pre- and postsynapse1, but our understanding of the essential organizational molecules involved in this process remains incomplete2. Teneurin proteins are conserved, epidermal growth factor (EGF)-repeat-containing transmembrane proteins with large extracellular domains3. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic whereas Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization trans-synaptically and cell autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with α-Spectrin. Genetic analyses of teneurin and neuroligin reveal that they have differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates target selection between specific motor neurons and muscles. Our study identifies the Teneurins as a key bi-directional trans-synaptic signal involved in general synapse organization, and demonstrates that proteins such as these can also regulate target selection.

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Figure 1: Teneurins are enriched at and interact across Drosophila neuromuscular synapses.
Figure 2: Teneurins affect the structure and function of the neuromuscular synapse.
Figure 3: Teneurin perturbation results in marked cytoskeletal disorganization.
Figure 4: High-level Ten-m expression regulates muscle target selection.

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Acknowledgements

We thank H. Aberle, V. Budnik, A. DiAntonio, R. Dubreuil, D. Featherstone, N. Reist, T. Schwarz, S. Stowers, D. Van Vactor, R. Wides, the Bloomington Stock Center and the Developmental Studies Hybridoma Bank for fly stocks, antibodies and reagents; J. Perrino and D. Luginbuhl for technical assistance; K. Shen, K. Zinn, D. Banovic, D. Berns, Y. Chou, C. A. Frank, X. Gao, S. Hippenmeyer, K. Miyamichi, K. Sillar, B. Tasic, X. Yu and S. Zosimus for critiques. Supported by a National Institutes of Health (NIH) grant (R01 DC-005982 to L.L.), and Epilepsy, Neonatology and Developmental Biology Training Grants (NIH 5T32 NS007280 and HD007249 to T.J.M.). L.L. is an investigator of the Howard Hughes Medical Institute.

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T.J.M. designed and performed all experiments (apart from electrophysiology). W.H. characterized and provided new reagents, and assisted in some experiments. V.S.D. and T.J.M. designed and V.S.D. performed electrophysiology experiments with assistance from T.J.M. V.F. provided new reagents. L.L. supervised the project. T.J.M. wrote the manuscript with feedback from all authors.

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Correspondence to Timothy J. Mosca.

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Mosca, T., Hong, W., Dani, V. et al. Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice. Nature 484, 237–241 (2012). https://doi.org/10.1038/nature10923

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