Uncovering the role of the ESCRT machinery in neuron pruning

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Like a computer or any other complex electronic device our brain needs to be accurately 'wired together' to function properly. Current thinking suggests that disruptions in wiring may underlie a number of psychiatric disorders, so to understand how wiring in the nervous system goes wrong is very important for aiding therapeutic approaches for such disorders. As such this work is likely to contribute to the healthcare sector and thus to our society. As the nervous system forms, nerve cells grow to make connections with one another and as such are like the wires of an electrical device. When nerve cells grow, they do so in an exuberant manner, often generating many extension branches. Some of these branches enter the wrong territory or are redundant and need to be removed. We call this removal of branches 'pruning'. Pruning of excess or redundant branches is important for adjusting the nervous system so that it can work with precision. In many cases pruning happens by branches being cut off, hence the term 'pruning'. Although we know a great deal about how the nervous system develops, our understanding of how branches are physically cut away remains a mystery. We have been using the fruitfly Drosophila to try and answer this question. We use flies because they share most of their genes with humans, so what we learn in the fly can be easily translated to humans. At the same time, fruitflies have a relatively simple nervous system that is more accessible and easier to study than more complex nervous systems as found in mouse. Flies are perfect for applying genetics to investigate their biology. For example, fruitflies grow quickly so one can do genetic screens; ie. breaking genes, which is a powerful way uncovering how things work. In this project we are focusing on pruning in the nervous system. Here, the fly provides a great opportunity, as many of its nerve cells are recycled during metamorphosis, when a maggot turns into a fly. Pruning is important for the recycling process. We study how nerve cells undergo pruning by using fluorescent 'glowing' genes from a jellyfish, which allows us to see nerve cells inside the living animal. Using these glowing nerve cells and fly genetics we found that a family of proteins called the Endosomal Sorting Complexes Required for Transport (ESCRT) are important for pruning. These ESCRT proteins assemble and together form a machine that cuts cell membranes. Because cells are really a large system of membranes containing different components, this group of proteins is important and used for many different processes in different parts of cells e.g. they are also used when cells divide in two. To schedule these proteins for each specific task, they have very specific adaptors that direct them to work in the right place at the right time. We think that something like the cutting that occurs when a cell divides is also happening during nerve cell branch pruning. We are the first people to have any evidence to suggest that the ESCRT machinery is involved in cutting nerve cell branches. Because this observation gives us a new clue as to the genes and mechanisms that regulate pruning in the nervous system, this is a very important observation. We would now like to confirm these observations and extend them. We want to know which of the ESCRT family members are important for pruning and which are not; how these machines assemble, whether they are actually needed directly at the place where the branch is cut and how the cutting process is controlled by the adaptors. We hope our work will resolve part of this mystery and that in future the new insights that our work can help up understand what happens when wiring goes wrong in human disorders of the nervous system, and, by extension what therapeutic approaches could be developed to correct such defects or lessen their impact on mental health and well being.