C. elegans Punctin Clusters GABAA Receptors via Neuroligin Binding and UNC-40/DCC Recruitment

• Published in: Neuron (Cambridge, Mass.) Vol. 86; no. 6; pp. 1407 - 1419
• Main Authors: Tu, Haijun, Pinan-Lucarré, Bérangère, Ji, Tingting, Jospin, Maelle, Bessereau, Jean-Louis
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 17.06.2015
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.05.013

Positioning type A GABA receptors (GABAARs) in front of GABA release sites sets the strength of inhibitory synapses. The evolutionarily conserved Ce-Punctin/MADD-4 is an anterograde synaptic organizer that specifies GABAergic versus cholinergic identity of postsynaptic domains at the C. elegans neuromuscular junctions (NMJs). Here we show that the Ce-Punctin secreted by GABAergic motor neurons controls the clustering of GABAARs through the synaptic adhesion molecule neuroligin (NLG-1) and the netrin receptor UNC-40/DCC. The short isoform of Ce-Punctin binds and clusters NLG-1 postsynaptically at GABAergic NMJs. NLG-1 disruption causes a strong reduction of GABAAR content at GABAergic synapses. Ce-Punctin also binds and localizes UNC-40 receptors in the postsynaptic membrane of NMJs, which promotes the recruitment of GABAARs by NLG-1. Since the mammalian orthologs of these genes are expressed in the central nervous system and their mutations are implicated in neuropsychiatric diseases, this molecular pathway might have been evolutionarily conserved. •Ce-Punctin is an anterograde organizer of C. elegans GABAergic synapses•Ce-Punctin is a new ligand of NLG-1/neuroligin and triggers its synaptic clustering•Ce-Punctin binds and localizes UNC-40/DCC receptors at synapses•UNC-40/DCC signaling promotes the recruitment of GABAA receptors by NLG-1/neuroligin Here Tu et al. uncover a pathway that controls the clustering of GABA receptors and identify the neurally secreted anterograde organizer Ce-Punctin as a ligand of NLG-1/neuroligin.