SNARE-Mediated Exocytosis in Neuronal Development

The formation of the nervous system involves establishing complex networks of synaptic connections between proper partners. This developmental undertaking requires the rapid expansion of the plasma membrane surface area as neurons grow and polarize, extending axons through the extracellular environment. Critical to the expansion of the plasma membrane and addition of plasma membrane material is exocytic vesicle fusion, a regulated mechanism driven by soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNAREs). Since their discovery, SNAREs have been implicated in several critical neuronal functions involving exocytic fusion in addition to synaptic transmission, including neurite initiation and outgrowth, axon specification, axon extension, and synaptogenesis. Decades of research have uncovered a rich variety of SNARE expression and function. The basis of SNARE-mediated fusion, the opening of a fusion pore, remains an enigmatic event, despite an incredible amount of research, as fusion is not only heterogeneous but also spatially small and temporally fast. Multiple modes of exocytosis have been proposed, with full-vesicle fusion (FFV) and kiss-and-run (KNR) being the best described. Whereas most in vitro work has reconstituted fusion using VAMP-2, SNAP-25, and syntaxin-1; there is much to learn regarding the behaviors of distinct SNARE complexes. In the past few years, robust heterogeneity in the kinetics and fate of the fusion pore that varies by cell type have been uncovered, suggesting a paradigm shift in how the modes of exocytosis are viewed is warranted. Here, we explore both classic and recent work uncovering the variety of SNAREs and their importance in the development of neurons, as well as historical and newly proposed modes of exocytosis, their regulation, and proteins involved in the regulation of fusion kinetics.