Neurite outgrowth: this process, first discovered by Santiago Ramon y Cajal, is sustained by the exocytosis of two distinct types of vesicles.

Neurite outgrowth is a fundamental process in the differentiation of neurons. The first, seminal study documenting the generation of "appendages" (now known as filopodia and lamellipodia) on the "cones d'accroissement," the specialized growth cones at the tips of neurites, was reported by Cajal still in the XIXth century, investigating chicken neurons embryos stained by the Golgi's reazione nera. Since then, studies have continued using, in addition to brain tissues, powerful in vitro models, i.e. primary cultures of pyramidal neurons from the hippocampus and neurosecretory cell lines, in particular PC12 cells. These studies have documented that neuronal neurites, upon sprouting from the cell body, give rise to both axons and dendrites. The specificity of these differentiated neurites depends on the diffusion barrier established at the initial segment of the axon and on the specialized domains, spines and presynaptic boutons, assembled around complexes of scaffold proteins. The two main, coordinate mechanisms that support neurite outgrowth are (a) the rearrangement of the cytoskeleton and (b) the expansion of the plasma membrane due to the exo/endocytosis of specific vesicles, distinct from those filled with neurotransmitters (clear and dense-core vesicles). The latter process is the main task of this review. In axons the surface-expanding exocytoses are concentrated at the growth cones; in dendrites they may be more distributed along the shaft. At least two types of exocytic vesicles appear to be involved, the enlargeosomes, positive for VAMP4, during early phases of development, and Ti-VAMP-positive vesicles later on. Outgrowth studies, that are now intensely pursued, have already yielded results of great importance in brain cell biology and function, and are playing an increasing role in pathology and medicine.