The neuron is the basic unit of the nervous system, which allows organisms to sense, memorize, think, and respond to the world. The function of the neuron relies on its proper polarization and compartmentalization in order to receive signals from the right field, process information, and transmit it to the correct target. To understand the molecular mechanisms underlying how presynaptic components like synaptic vesicles (SVs) and active zone proteins are localized to defined axonal domains, an unbiased visual forward genetic screen was performed to identify genes controlling the localization of GFP::RAB3, a specific synaptic vesicle marker, in the cholinergic motor neuron DA9 in C. elegans. Two cyclin-dependent kinases (CDKs), CDK-5 and PCT-1, and their specific activators
p35/CDKA-1 and CYY-1 respectively were identified as key regulators for axon-dendrite polarization of presynaptic components. The loss of both PCT-1 and CDK-5 activity caused nearly all synapic vesicles and active zone proteins ectopically accumulated in dendrites. To identify downstream components, the
cdk-5 modifier screen was performed that revealed the dynein-mediated retrograde transport and clathrin-mediated endocytic machinery were necessary for the polarity phenotype. Further characterization of CDK-5 and PCT-1 indicated that CDK-5 is mainly localized at the presynaptic terminals, while CYY-1, acting as the activator of PCT-1, is enriched in dendrites. Overexpression of PCT-1, but not CDK-5, eliminated proximal presynaptic clusters. In contrast, the
cdk-5 mutant, but not the
pct-1 mutant, has imbalanced polarized SV trafficking at the proximal axon. Based on these data we propose that CDK-5 acts in the presynaptic domain to guide polarized SV trafficking and PCT-1 is activated by CYY-1, which prevents SV clusters from stabilizing in dendrites.