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

• Published in: Nature neuroscience Vol. 12; no. 4; pp. 428 - 437
• Main Authors: Kwon, Seok-Kyu, Woo, Jooyeon, Dunah, Anthone W, Kim, Eunjoon, Lee, Jae-Ran, Kim, Seho, Choi, Seungwon, Sheng, Morgan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2009; Nature Publishing Group
• Subjects: Analysis of Variance; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell adhesion molecules; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - physiology; Cell Differentiation - physiology; Cells, Cultured; Cellular proteins; Coculture Techniques - methods; Embryo, Mammalian; Gene Expression Regulation, Developmental - physiology; Genetic aspects; Genetic regulation; Green Fluorescent Proteins - genetics; Hippocampus - cytology; Humans; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurons - cytology; Neurosciences; Physiological aspects; Presynaptic Terminals - metabolism; Rats; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - physiology; Receptors, Cell Surface - genetics; Synapses; Synapses - classification; Synapses - physiology; Synaptic Transmission - genetics; Synaptic Transmission - physiology; Transfection - methods; Vesicular Inhibitory Amino Acid Transport Proteins - metabolism; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2279

Although the receptor tyrosine phosphatase LAR is known to regulate the devolvement of excitatory synapse and to direct proper guidance of axons, the extracellular ligand for its activation has remained unknown. This study identifies postsynaptic netrin G-ligand 3 (NGL-3) as the trans-synaptic adhesion ligand of LAR and demonstrates a bidirectional regulation of excitatory synapse formation by the LAR/NGL-3 interaction. 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.