Feline Lindhout

156 5 3 . Thus, human iPSC-derived neurons offers the great advantage of studying neurobiology on a human genetic background, which may contribute to new insights that will perhaps further our understanding of the development of axonal pathologies and other neurological disorders. Another future challenge in the field of axon biology is to unravel the precise coordination of the different molecular machineries that facilitate neuronal communication. More specifically, it would be interesting to gain an advanced understanding on how the functioning of presynaptic organelles, such as axonal ER and mitochondria, are integrated with neurotransmitter release. To this end, novel insights will likely come from newly developed tools that allow in-depth investigations of the structure and function of axonal organelles. Accordingly, high resolution imaging recently enabled resolving the nanostructures of the axonal ER network, thereby uncovering its unique organization and continuity with the remaining ER network (Yalcin et al. 2017; Wu et al. 2017; Terasaki 2018). What could be the functional implication of this unique axonal ER network? Is perhaps the continuity of the axonal ER with the somatodendritic ER network important for processes underlying axon functioning, such as neurotransmitter release? Future investigations with recently developed tools to measure organelle functions, e.g. by measuring intra-luminal Ca 2+ levels in ER or mitochondria, will likely address these and other urgent questions (de Juan-Sanz et al. 2017). It will be exciting to learn in the coming years how the well-defined processes of the synaptic vesicle cycle can be mechanistically tweaked by axonal organelles. Taking together, a combination of multidisciplinary approaches, application of newly developed tools, and the accessibility of different neurobiological model systems, thereby carefully taking into consideration the strengths and limitations of each model system, now allows addressing new questions in the field of axon biology. A thorough understanding of the basic principles of axon formation and function is key, as this might provide an important stepping stone in dissecting and ultimately resolving axonopathies. ACKNOWLEDGEMENTS I would like to thank Sybren Portegies for co-producing the illustrations, and Harold MacGillavry and Robbelien Kooistra for their constructive feedback on the text.