How do glia remodel the nervous system?

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Project Summary A common feature of nervous systems is that they are initially overpopulated with neurons and over-wired, initially generating an excessive number of synaptic connections. This is followed by an essential period of remodeling whereby a subset of extraneous neurons or synaptic connections are removed in order to optimize function in the adult nervous system. The elimination of cells and pruning of synapses is a process coordinated by neurons and glia. The selection of specific connections or cells for elimination seems to involve a conversation between neurons and glia, and the clearance of debris from the nervous system is performed predominantly by phagocytic glial cells. Previous research has highlighted that the nervous system uses a diversity of molecules and mechanisms to identify engulfment targets, which appear to be context-specific. However, major gaps still exist in our knowledge of how neurons identify themselves to be remodeled and how glial cells recognize these dying or pruning neurons. Studying these processes can potentially lead us to a better understanding of mechanisms underlying neurodevelopmental disorders such as Autism Spectrum Disorders and Schizophrenia. Our lab has employed Drosophila as a model system for several reasons including the powerful genetic tools and the stereotyped nature of one of its remodeling periods—metamorphosis. Through transcriptomic profiling in phagocytic astrocytes, I identified the transmembrane immunoglobulin superfamily gene borderless. My preliminary data suggests that Bdl is highly expressed in astrocytes during engulfment periods early in metamorphosis. Interestingly, loss of both Borderless (Bdl) and the known engulfment receptor Draper (MEGF10 in mammals) resulted in strong suppression of astrocyte engulfment of synapses and neurites. Bdl has been described to interact with a closely related protein named Turtle, and my preliminary data further suggests Turtle is specifically localized to neurites and synapses, and excluded from the cell body (the only compartment of the cell that astrocytes do not engulf). Turtle may therefore act as a molecular tag for astrocytes to recognize appropriate engulfment targets. In Aim 1 of this study, I will characterize Bdl expression in astrocytes, explore genetic interactions between Bdl and Draper, and determine which domains of Bdl are essential for engulfment activity. In Aim 2, I will 1) define genetic interactions between Bdl, Turtle, and Draper, 2) determine the cell autonomy of Bdl and Turtle in the remodeling of corazonin neurons and 3) determine the subcellular localization of Turtle positing me to explore Turtle as a molecular tag for specifying neurites for engulfment. My work has the potential to define two novel components of the astrocytic engulfment machinery, (Bdl and Turtle), explore how they converge with Draper/MEGF10, and identify Turtle as a neurite/synapse-specific molecular tag that directly directs astrocyte engulfment activity. This work will significantly advance our understanding of the molecular basis of neuron-glia signaling during neuronal remodeling, which will be essential for us to understand and treat neurodevelopmental disorders in humans.