Selective regulation of transsynaptic alignment and postsynaptic assembly by a novel NCAM family synaptic adhesion molecule

Synapse formation underlies the organization of neurons into functional circuits during brain development and requires precise alignment and maturation of pre-and postsynaptic compartments. Many synaptogenic adhesion molecules have been identified that drive target recognition and sustained adhesion between appropriate synaptic partners. Yet the degree to which individual molecules serve selective functions in distinct aspects of synapse formation and maturation remains poorly understood. In particular, how exquisite nanoalignment of pre-and postsynaptic specializations flows from micron-scale adhesive interactions between synaptic partners remains a key unanswered question. Here we shed new light on this question by establishing a specialized set of synaptic functions for <i>Epithelial limiter of Fasciclin II function (Elff</i> ), an NCAM family member with previously unknown roles in the nervous system. Our structural and functional studies at the glutamatergic Drosophila NMJ indicate that Elff is required for postsynaptic assembly, maturation, and transsynaptic alignment; however, it is not required for presynaptic function, bouton formation, or developmental expansion of the NMJ. Notably, NMJs in <i>elff</i> null mutants display reduced glutamate receptor clustering beginning at the embryonic stage when NMJ synapses first form. These poorly defined postsynaptic specializations are frequently out of register with presynaptic release sites, disrupting neurotransmission. Unexpectedly, the striking defects in <i>elff</i> nulls occur in the context of both normal active zone number and developmental expansion of the NMJ. These findings suggest a surprising degree of specialization among transsynaptic adhesion complexes and demonstrate that Elff-mediated signaling is critical for the transsynaptic nanoarchitecture of glutamatergic synapses.