[SY7.0]: Roles of endosomes in presynaptic differentiation

Presynaptic differentiation involves a cohort change in vesicular and cytoskeletal dynamics, resulting in the accumulation of synaptic vesicles docked around the electron-dense specializations at the plasma membrane. Using forward genetics, we have identified two C. elegans proteins, RPM-1 and UNC-16, in promoting presynaptic differentiation. RPM-1 is a member of the conserved PHR protein family, which are large proteins containing a Ring-finger E3 ubiquitin ligase domain and an RCC1 homology (RLD) GEF domain. UNC-16 is a member of the JIP3 family that is implicated as kinesin adaptors. We show that RPM-1 acts as an E3 ubiquitin ligase to negatively regulate a MAP kinase cascade, which transduces retrograde signaling from synapse to nucleus. RPM-1 also interacts with an RLD containing RabGEF protein to positively regulate an AP3-dependent late endosomal compartment in synapse and axon stabilization. We further show that UNC-16 regulates synaptic vesicle maturation through a RAB5 compartment. Our on-going studies reveal a multi-layered regulation of synaptic endosomes in presynaptic differentiation.