Extracellular heparan sulfate proteoglycans and glycan-binding lectins orchestrate -synaptic signaling.

The exceedingly narrow synaptic cleft (<20 nm) and adjacent perisynaptic extracellular space contain an astonishing array of secreted and membrane-anchored glycoproteins. A number of these extracellular molecules regulate intercellular -synaptic signaling by binding to ligands, acting as co-receptors or modulating ligand-receptor interactions. Recent work has greatly expanded our understanding of extracellular proteoglycan and glycan-binding lectin families as key regulators of intercellular signaling at the synapse. These secreted proteins act to regulate the compartmentalization of glycoprotein ligands and receptors, crosslink dynamic extracellular and cell surface lattices, modulate both exocytosis and endocytosis vesicle cycling, and control postsynaptic receptor trafficking. Here, we focus closely on the glutamatergic neuromuscular junction (NMJ) as a model synapse for understanding extracellular roles of the many heparan sulfate proteoglycan (HSPG) and lectin proteins that help determine synaptic architecture and neurotransmission strength. We particularly concentrate on the roles of extracellular HSPGs and lectins in controlling -synaptic signaling, especially that mediated by the Wnt and BMP pathways. These signaling mechanisms are causally linked to a wide spectrum of neurological disease states that impair coordinated movement and cognitive functions.