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Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses

Nature Neuroscience volume 12, pages 428–437 (2009)Cite this article

Abstract

Synaptic adhesion molecules regulate multiple steps of synapse formation and maturation. The great diversity of neuronal synapses predicts the presence of a large number of adhesion molecules that control synapse formation through trans-synaptic and heterophilic adhesion. We identified a previously unknown trans-synaptic interaction between netrin-G ligand–3 (NGL-3), a postsynaptic density (PSD) 95–interacting postsynaptic adhesion molecule, and leukocyte common antigen-related (LAR), a receptor protein tyrosine phosphatase. NGL-3 and LAR expressed in heterologous cells induced pre- and postsynaptic differentiation in contacting axons and dendrites of cocultured rat hippocampal neurons, respectively. Neuronal overexpression of NGL-3 increased presynaptic contacts on dendrites of transfected neurons. Direct aggregation of NGL-3 on dendrites induced coclustering of excitatory postsynaptic proteins. Knockdown of NGL-3 reduced the number and function of excitatory synapses. Competitive inhibition by soluble LAR reduced NGL-3–induced presynaptic differentiation. These results suggest that the trans-synaptic adhesion between NGL-3 and LAR regulates excitatory synapse formation in a bidirectional manner.

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Figure 1: NGL-3 expressed in non-neural cells induces functional presynaptic differentiation in contacting axons.
Figure 2: Expression patterns of NGL-3 proteins in rat brain.
Figure 3: Overexpression of NGL-3 in cultured neurons increases excitatory, but not inhibitory, presynaptic contacts on dendrites of transfected neurons.
Figure 4: Direct aggregation of NGL-3 on the surface of dendrites induces coclustering of excitatory postsynaptic proteins.
Figure 5: Knockdown of NGL-3 leads to decreases in the number and function of excitatory synapses.
Figure 6: NGL-3 interacts with LAR.
Figure 7: Soluble LAR reduces NGL-3–induced presynaptic differentiation.
Figure 8: LAR expressed in non-neural cells induces excitatory postsynaptic differentiation in contacting dendrites.

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Acknowledgements

We would like to thank A.M. Craig for neurexin 1α, 2α, 3α and 1β cDNAs, T. Biederer for SynCAM 1, Y.-P. Hsueh for Syndecan-2, P. Maness for NCAM-140, J. Ko for quantitative analysis, J. Nam for SALM4, M.-H. Kim for the mini analysis program, and Y.-G. Oh, M.-S. Baek, M. Ryu and J.-G. Jung for the help with antibody generation. This work was supported by the National Creative Research Initiative Program of the Korean Ministry of Science and Technology (E.K.).

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  1. Jooyeon Woo and Seok-Kyu Kwon: These authors contributed equally to this work.

Authors and Affiliations

  1. National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea

    Jooyeon Woo, Seok-Kyu Kwon, Seungwon Choi, Seho Kim, Jae-Ran Lee & Eunjoon Kim

  2. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

    Anthone W Dunah

  3. The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Morgan Sheng

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Contributions

J.W. and S.-K.K. carried out the experiments, analyzed the data and wrote the manuscript. S.C. helped with the shRNA knockdown experiments. S.K., J.-R.L., A.W.D. and M.S. contributed reagents. E.K. supervised the project and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Eunjoon Kim.

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Woo, J., Kwon, SK., Choi, S. et al. Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses. Nat Neurosci 12, 428–437 (2009). https://doi.org/10.1038/nn.2279

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