Neurons represent an extreme example of polarized cells. This polarization arises because, during differentiation, neurons generate cytoplasmic extensions, designated as axons and dendrites, which acquire highly elaborated shapes and differ in cytoskeletal organization, organelle content and plasma membrane lipid and protein composition.

Axons and dendrites are crucial for the development and maturation of the nervous system, as the establishment of precise synaptic connections (e.g. brain wiring), and hence the appropriate functioning of brain circuits, is totally dependent on their elaboration and maintenance.

Cytoskeletal assembly and membrane trafficking are two key events underlying the generation of axons and dendrites. The extension of axons and dendrites requires the continuous addition of a very large quantity of new membrane to the neuron plasmalemma. The membrane for the plasmalemmal expansion is generated through the secretory pathway, and via lipid transfer between the endoplasmic reticulum (ER) and the plasma membrane.

The secretory vesicles involved in this growth are primarily generated in the neuron's perikaryon, and then transported by microtubular motors as plasmalemmal precursor vesicles (PPVs) to the cell periphery where they will be incorporated into the cell membrane and, perhaps, expel their contents to the exterior of the cell.

Lipid transfer between the ER and the plasma membrane can occur at several locations in neurons but appears particularly in growth cones, highly dynamic specialized structures at the tip of extending axons. Furthermore, certain membrane proteins and lipids are synthesized in the axonal growth cone, but how locally synthesized membrane proteins are inserted into the plasma membrane is unknown.

Exocytotic insertion of plasmalemmal precursor vesicles at the axonal growth cone is different from the one aimed to the release of synaptic vesicles. In fact, not only it requires the involvement of vesicle trafficking protein complexes, such as exocyst and SNARE proteins, but it is also regulated locally.

The coordinated activity of microtubular motors, exocyst and SNARE protein complexes is regulated by both intrinsic signaling mechanisms and extracellular clues, such as neurotrophins and growth factors.

There is solid published evidence suggesting that membrane expansion at the axonal growth cone and the regulation of initial axonal elongation are not just a read-out of polarity but an essential step in its establishment. However, many questions about the involvement of plasmalemmal expansion in axonal specification and initial axonal elongation necessary for the establishment of neuronal polarity remain open.

The study of membrane biogenesis and trafficking in developing neurons is now at a particularly exciting time when new genetic tools and imaging approaches allow to understand in greater details how neurons can grow meters long processes. This knowledge will be crucial in all therapeutic strategies aimed at regenerating neurons and reconstructing connections in the brain.

We expect that the collaborations within this Research Topic can shed new light about the regulation of the mechanisms involved in plasmalemmal synthesis, assembly, transport, and exocytic incorporation during neuronal differentiation and/or regeneration.

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Frontiers in Molecular Neuroscience

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