Non-Canonical Roles for Cell-Adhesion Molecules in Presynaptic Assembly

PROJECT SUMMARY The proper formation of synapses is integral to the function of neural circuits. Disruptions in synaptogenesis during early development can lead to neurodevelopmental disorders, such as autism or intellectual disability. Yet despite decades of study, precisely how synapses form, mature, and are maintained has remained elusive. Cell-adhesion molecules (CAMs) have been implicated in synaptogenesis, as their extracellular trans- synaptic interactions are capable of inducing synapse assembly and conferring synaptic partner specificity. However, the intracellular signaling pathways that mediate their synaptogenic functions are less understood. Using the roundworm C. elegans, we have identified a pair of CAMs, SYG-1 and SYG-2, that may have non- canonical roles in synapse assembly, functioning in the absence of trans-synaptic binding to regulate presynaptic assembly. We have found that the intracellular domain of SYG-2 alone is sufficient for inducing presynaptic assembly, in contrast to the accepted idea that the extracellular domains of CAMs are required for their function. Using CRISPR transgenesis, I will determine whether this protein and its known binding partner SYG-1 are required together or separately to organize presynaptic specializations. I will then mutate candidate binding motifs within their intracellular domains to elucidate the downstream intracellular pathways required for their function. These experiments will provide insight into the possible function and underlying mechanisms of SYG-1/SYG-2 human ortholog KIRREL3, which has been implicated in autism.