Genetic analysis of the adenylate forming domain protein DIP-2 in C. elegans neuronal development

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Neurons exhibit a diverse array of morphologies that contribute to both connectivity and function. Neuronal morphology is established during critical developmental periods when cytoskeletal structures and rearrangements mediate the specification of axon and dendritic processes, wiring of neuronal connections and the activity-dependent and independent elaboration of dendritic arbours. Post-developmentally, neurons are very long lived and, while shown to be capable of plasticity-promoting remodeling of dendritic structures, are thought to maintain relatively stable morphologies over adulthood. The molecular mechanisms that maintain neuronal morphology remain poorly understood. My lab is interested in how neuronal morphology is established and maintained using the anatomically simple nervous system of C. elegans, a microscopic worm, as a model system. We have recently found that mutations in dip-2, the worm orthologue of Disco Interacting Protein-2 (DIP2), display strong neuronal morphology defects in multiple types of neurons suggesting a central role in both nervous system development and maintenance. DIP2 proteins belong to a highly conserved but poorly understood family of adenylate forming domain proteins. Our objective with this Discovery Grant is to understand how the adenylate forming domain protein DIP-2 acts to maintain neuronal morphology. First, we propose to undertake unbiased gene/protein discovery' approaches to identify mutations in genes that display dip-2-like neuronal morphology defects or aberrant DIP-2 protein localization (Aim 1A) and new components of DIP-2 protein complexes in neurons (Aim 1B) and second, characterize the resulting genes/protein candidates for direct roles in DIP-2 mediated neuronal maintenance (Aim 2). Successful completion of these aims should lead to fundamental insight into how neurons maintain their morphology during the normal aging process.