| Neurons are prime examples of highly polarized cells that receive information through their dendrites and output is sent through their axons. Though the selective localization of synaptic proteins to axons or dendrites is crucial for neuronal function, little is known about this process. The localization of presynaptic components, in particular, is poorly understood. Several intrinsic factors have been shown to regulate transport of axonal and dendritic proteins but their functions in vivo are unclear. In addition, the role of extracellular cues in this process has not been explored.;To identify other factors important for localizing synaptic components, we conducted forward genetic screens. We identified a novel cyclin ZK353.1 and PCT-1, a Pctaire kinase similar to cyclin-dependent kinases (CDKs), both of which exclude presynaptic components from the dendrite. Through a biochemical approach, we observed that ZK353.1/cyclin associates with and activates PCT-1. Upon investigation of other CDKs, we found that CDK-5 and its activator CDKA-1/p35 also exclude presynaptic components from the DA9 dendrite. Genetic interaction studies suggest that ZK353.1/cyclin and PCT-1 act in parallel with CDK-5 and CDKA-1/p35. In addition, both CDKs are likely to act through the kinesins UNC-116/KHC and UNC-104/KIF1A. These findings indicate a novel and significant role for two CDKs in excluding presynaptic components from the dendrite. We are currently addressing if these novel factors act downstream of netrin and/or Wnt.;Our studies have provided insight into mechanisms underlying the polarized distribution of presynaptic components in vivo, a crucial step in nervous system development. Extracellular cues may act through novel intrinsic signaling pathways to regulate the localization of presynaptic components.;To address how presynaptic components are localized in vivo, we studied the C. elegans motor neuron DA9. We found that the absence of the guidance cue UNC-6/netrin or its receptor UNC-5 results in the mislocalization of presynaptic components to the DA9 dendrite. Our findings suggest that endogenous UNC-6/netrin present near the DA9 dendrite excludes presynaptic components from this compartment throughout development. Interestingly, the antisynaptogenic activity of UNC-6/netrin is interchangeable with that of LIN-44/Wnt despite being transduced through different receptors, suggesting that extracellular cues such as Netrin and Wnts not only guide axon navigation but also regulate the polarized accumulation of presynaptic components through local exclusion. |
