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Building a synapse [electronic resource] : from extracellular cues to intracellular proteins

Nervous system function, from sensory perception to motor control, requires precisely patterned networks of synaptic connections. Each synapse is the fundamental unit of connection and proper establishment of this complex structure is essential for cognitive processes. Therefore, elucidating the molecular mechanisms and characterizing the proteins important for the development and structural organization of a synapse is fundamental to our understanding of the brain. Using C. elegans, I have explored the process of presynaptic development for my thesis work. I demonstrate that specification and initiation of synapse formation by clustering of SYG-1/Neph and SYG-2/Nephrin, two immunoglobulin superfamily transmembrane proteins, is dependent on their cell adhesion strength and interaction topology during development. Once this extracellular instructive cue is established at nascent synapses, an Arp2/3 dependent actin cytoskeleton is built locally that is dependent on the WVE-1/WAVE regulatory complex (WRC). This is mediated by interaction between a WRC interacting receptor sequence (WIRS) motif on the intracellular tail of SYG-1, which recruits the WRC. Next, an adaptor protein NAB-1/Neurabin binds to F-actin and recruits active zone proteins, SYD-1 and SYD-2/Liprin-[alpha] by forming a tripartite complex. SYD-2/Liprin-[alpha] is a key scaffold protein that interacts with multiple active zone components including UNC-10/Rim, ERC/ELKS-1, and GIT to form the synaptic active zone. SYD-2/Liprin-[alpha]'s pro-synaptogenic function can be regulated by interaction between its N-terminal coiled-coil domains and C-terminal sterile alpha motif (SAM) domains. Taken together, this insight into how synapses assemble in a simpler organism may lead to better understanding of development and function of the mammalian brain and its dysfunction in disease.