Mechanism of autophagy-controlled axon branching

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One of the most important unsolved questions for scientists is how the nervous system is formed. During embryonic development nerve cells send out long thread-like structures, or axons, which grow over long distance to reach their destinations, where they will wire up with other nerve cells. In order to form connections with multiple other nerve cells, axons must branch in the target area which follows an intricate and specific pattern. This process is crucial for the development of neuronal circuits. Our research seeks to understand axon branching in the visual system, which connects the retina of the eye with the brain. The large body of knowledge accrued about the visual system makes it ideal for uncovering fundamental principles of development. Our previous work has shown that when retinal neurons are cultured, they form branched patterns which are closely similar to those found in the intact organism. We have recently found that the neuron's waste disposal processes, termed autophagy, is involved in this process. Neurons deploy autophagy as a means of degrading unwanted molecules. We have shown that an increase in autophagy leads to an increase in the number of branches, while a reduction autophagy leads to a decrease in the number of branches. We believe that neurons control the number and location of branches by locally destroying (via autophagy) molecules which normally suppress the formation of axon branches. Thus during development, axon branching is normally suppressed, and only in regions where autophagy is activated, branching can occur. We have shown that a small molecule called Arl8B, which transports lysosomes in axons, might control where autophagy is activated. Changes in the expression level of Arl8B correlate with changes in the distribution and density of vesicles having a key role in executing autophagy, named autophagosomes. This exciting project will test the hypothesis that autophagy shapes axonal branching and neural circuit development. Our data so far show a good correlation, and we aim to show now a causal relationship. For this we will use time lapse experiments to unravel the spatio-temporal correlation between the movement of autophagosomes/lysosomes and the formation of branches. Then we would like to identify the extracellular molecules which control where along an axon autophagy is activated, and we would like to identify the suppressor molecules which normally block branching. This work on neuronal cell culture will be extended into intact animals. We would like to show for individual axons that genetically eliminating autophagy in the retina disturbs their connectivity in the visual system of mice. This will suggest that the mechanisms we have discovered in culture play a role during the development of the visual system. We think that an integration of these interwoven approaches will lead to a deeper understanding of the role of autophagy and one of its key components, Arl8B, in circuit development within the nervous system. Up to now, very little is known about the role of autophagy during nervous system development, and our research will provide substantial new information on these issues. Recent publications have uncovered a close link between deregulation of autophagy and the aetiology of autism spectrum disorders. We predict that our investigation of the small G protein Arl8B will integrate these different aspects into one concept, and represents a novel approach to investigate the connection between autophagy and neural circuit formation. We predict that this investigation will contribute to a better understanding of the aetiology of autism spectrum disorders.