Chemical synapses are specialized cellular junction structures that are essential for communication between neurons. During development, synapses form between specific neurons at defined subcellular compartments. Synaptic target selection, axonal transport and presynaptic assembly are integral steps of synapse formation that are poorly understood. Here, I propose to expand our research to understand two essential aspects of synapse formation: polarized axonal trafficking and how aggregation of active zone proteins is regulated. Synapses are usually formed on distal axon and dendrites, creating a challenging problem for effective exchange of intracellular material between cell bodies and synapses. Microtubules and MT associated motors mediate intracellular trafficking. It is generally believed that the direction of transport depends on two factors: the polarity of MTs and the type of motor involved. Based on our published and unpublished data, we have identified two cyclin-dependent kinase pathways that are essential for the trafficking of presynaptic components. In the absence of both pathways, the vast majority of synaptic vesicle proteins and active zone markers fail to localize to axon and instead are found in dendrites due to misregulation of kinesin motors. Another poorly understood question in synapse formation is how the pool size of synaptic vesicles is determined. Many synapses display stereotyped size of synaptic vesicle clusters, suggesting that molecular mechanisms regulate the assembly of synaptic vesicle precursors locally at the presynaptic terminals. When the appropriate number of vesicles is recruited, there might be a negative feedback system to shut down the assembly pathway. We reasoned that if this feedback mechanism is defective, one should expect to see mutant synapses with abnormal vesicle pool. Indeed in a forward genetic screen, we isolated a mutant in which the proximal synapses are abnormally large while the distal synapses contain little material. We have also identified an Arf like GTPase to be responsible for the regulation the location and size of presynaptic specializations. To gain mechanistic insights on the functions of these genes, I specifically plan to understand: 1) how the cyclin-dependent kinases pathways control axonal transport and synapse localization through the regulation of molecular motors, and 2) how an ARF like GTPase, ARL8 regulate the synaptic vesicle pool size and presynaptic assembly. Given that many neural disorders are associated with alterations in synaptic connectivity and that cyclin dependent kinases have been implicated in neurodegenerative diseases, it is hopeful that this project will help to understand brain development under both physiological and pathological conditions.
Synapses are critical for the communication between neurons. During synapse formation, proteins and vesicle are transported to presynaptic terminals in distal axons. The proposed study characterizes critical regulatory mechanisms for trafficking synaptic components to axons as well as locally synaptic assembly. This project will potentially shed light on the pathogenesis mechanisms of neurodegenerative diseases such as the Alzheimer's disease.
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