Regulation of synapse formation by selected SALM family proteins

Abstract

Synaptic cell adhesion molecules play critical roles in synapse formation. Synaptic adhesion-like molecules (SALMs) are members of a family of cell adhesion molecules; however, the role of SALMs in synapse formation remains unknown. I found that SALM3 and SALM5 induce both excitatory and inhibitory presynaptic differentiation in contacting axons, and knockdown of SALM5 reduces the number and function of excitatory and inhibitory synapses. In addition, I identified a novel trans-synaptic adhesion between SALM5 and LAR family receptor tyrosine phosphatases. LAR primarily mediates SALM5-dependent presynaptic induction, and the SALM5-LAR interaction is regulated by alternative LAR splicing. Importantly, SALM5 cis-interacts with and is stabilized by NGL-3, another adhesion molecule with presynapse-inducing activity, only when NGL-3 is occupied by its known ligand LAR. Coclustered NGL-3 and SALM5 cooperatively induce presynaptic differentiation. These results suggest that selected SALM family proteins regulate synapse formation and LAR-bound NGL-3 recruits SALM5 for cooperative presynaptic induction occurring mainly through the common ligand LAR.