GDNF and GFRα1 promote formation of neuronal synapses by ligand-induced cell adhesion

The establishment of synaptic connections requires precise alignment of pre- and postsynaptic terminals. The glial cell line derived neurotrophic factor (GDNF) receptor GFR alpha 1 is enriched at pre- and postsynaptic compartments in hippocampal neurons, suggesting that it has a function in synapse formation. GDNF triggered trans-homophilic binding between GFR alpha 1 molecules and cell adhesion between GFR alpha 1-expressing cells. This represents the first example of a cell-cell interaction being mediated by a ligand-induced cell adhesion molecule (LICAM). In the presence of GDNF, ectopic GFR alpha 1 induced localized presynaptic differentiation in hippocampal neurons, as visualized by clustering of vesicular proteins and neurotransmitter transporters, and by activity-dependent vesicle recycling. Presynaptic differentiation induced by GDNF was markedly reduced in neurons lacking GFR alpha 1. Gdnf mutant mice showed reduced synaptic localization of presynaptic proteins and a marked decrease in the density of presynaptic puncta, indicating a role for GDNF signaling in hippocampal synaptogenesis in vivo. We propose that GFR alpha 1 functions as a LICAM to establish precise synaptic contacts and induce presynaptic differentiation.