Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

The Drosophila proteins Neuroligin (Nlg1) and Neurexin (Nrx-1) form a trans-synaptic complex that regulates synapse formation at the neuromuscular junction. Here the authors show that Syd-1, also known to regulate active zone formation, interacts with presynaptic Nrx-1, promoting synaptic clustering and immobilization of Nrx-1, and subsequent glutamate receptor incorporation. Synapse formation and maturation requires bidirectional communication across the synaptic cleft. The trans-synaptic Neurexin-Neuroligin complex can bridge this cleft, and severe synapse assembly deficits are found in Drosophila melanogaster neuroligin (Nlg1 , dnlg1) and neurexin ( Nrx-1 , dnrx ) mutants. We show that the presynaptic active zone protein Syd-1 interacts with Nrx-1 to control synapse formation at the Drosophila neuromuscular junction. Mutants in Syd-1 ( RhoGAP100F , dsyd-1 ), Nrx-1 and Nlg1 shared active zone cytomatrix defects, which were nonadditive. Syd-1 and Nrx-1 formed a complex in vivo , and Syd-1 was important for synaptic clustering and immobilization of Nrx-1. Consequently, postsynaptic clustering of Nlg1 was affected in Syd-1 mutants, and in vivo glutamate receptor incorporation was changed in Syd-1 , Nrx-1 and Nlg1 mutants. S tabilization of nascent Syd-1–Liprin-α (DLiprin-α) clusters, important to initialize active zone formation, was Nlg1 dependent. Thus, cooperation between Syd-1 and Nrx-1–Nlg1 seems to orchestrate early assembly processes between pre- and postsynaptic membranes, promoting avidity of newly forming synaptic scaffolds.