Cizeron, Melissa, Zhou, Xin, Romatif, Oceane, Vachon, Camille, Jospin, Maelle, Bessereau, Jean-Louis, Bulow, Hannes E.
[
International Worm Meeting,
2021]
The extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1/Syndecan is a key organizer of the neuromuscular junctions (NMJs) and is the core component that clusters the homomeric alpha7-like nicotinic receptor ACR-16 at cholinergic NMJs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer MADD-4/Ce-Punctin. Punctin is secreted by cholinergic and GABAergic motoneurons into the synaptic cleft and triggers appropriate postsynaptic differentiation. We now show that Punctin has at least two parallel functions at cholinergic NMJs. First, it localizes the syndecan produced by muscle cells at postsynaptic sites. Second, it concentrates and likely activates the netrin receptor UNC-40/DCC. Those cooperatively recruit the FRM-3/FARP and LIN-2/CASK through direct interaction with the PDZ domain binding site of SDN-1 and the C-terminal P3 domain of UNC-40, respectively. The FERM-FA domain of FRM-3/FARP also engages direct interaction with SDN-1, likely with its submembrane C1 domain. The resulting CASK/FARP/Syndecan complex localizes N-AChRs at cholinergic NMJs through physical interactions. Interestingly, we were able to relocalize N-AChRs at GABAergic NMJs using a chimera containing the extracellular domain of the NLG-1/Neuroligin and the intracellular domain of SDN-1. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content. Surprisingly, the molecular mechanisms that control alpha7-like nicotinic receptors localization and dynamics are still largely unknown. Because all the components identified in C. elegans are evolutionarily conserved and expressed in mammalian neurons, our results provide a new framework to test if syndecan regulates the localization of nicotinic receptors in the mammalian brain.