The netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABA A receptors

• Published in: Nature communications Vol. 11; no. 1; p. 2674
• Main Authors: Zhou, Xin, Gueydan, Marine, Jospin, Maelle, Ji, Tingting, Valfort, Aurore, Pinan-Lucarré, Bérangère, Bessereau, Jean-Louis
• Format: Journal Article
• Language: English
• Published: England 29.05.2020
• Subjects: Animals; Axon Guidance - physiology; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - metabolism; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules, Neuronal - metabolism; Cytoskeletal Proteins - metabolism; Helminth Proteins - metabolism; Membrane Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neuromuscular Junction - metabolism; Receptors, Cell Surface - metabolism; Receptors, GABA-A - metabolism; Synapses - physiology; Synaptic Transmission - physiology
• ISSN: 2041-1723
• DOI: 10.1038/s41467-020-16473-5

Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation also play roles in synapse maturation and homeostasis. In C. elegans the netrin receptor UNC-40/DCC controls the growth of dendritic-like muscle cell extensions towards motoneurons and is required to recruit type A GABA receptors (GABA Rs) at inhibitory neuromuscular junctions. Here we show that activation of UNC-40 assembles an intracellular synaptic scaffold by physically interacting with FRM-3, a FERM protein orthologous to FARP1/2. FRM-3 then recruits LIN-2, the ortholog of CASK, that binds the synaptic adhesion molecule NLG-1/Neuroligin and physically connects GABA Rs to prepositioned NLG-1 clusters. These processes are orchestrated by the synaptic organizer CePunctin/MADD-4, which controls the localization of GABA Rs by positioning NLG-1/neuroligin at synapses and regulates the synaptic content of GABA Rs through the UNC-40-dependent intracellular scaffold. Since DCC is detected at GABA synapses in mammals, DCC might also tune inhibitory neurotransmission in the mammalian brain.