Exploring Role of Astrocytic adhesion GPCR Remoulade in Neuronal Remodeling - Project Summary Nervous systems are initially assembled with excess neurons and synaptic connections, but these are later refined whereby exuberant neurons, individual neurites, or synapses are eliminated, which is believed to drive optimization of neuronal circuitry for mature brain function. Failures in proper neuronal remodeling can result in significant neurodevelopmental disorders, including Autism Spectrum Disorders, schizophrenia, and epilepsy. Glial cells play a critical role in the circuitry refinement, helping neurons execute remodeling by removing neuronal debris, although the mechanisms mediating these processes are not well understood. To address this, I will explore the role of a novel pathway in Drosophilia, Remoulade (Remo), ortholog of the mammalian orphan adhesion GPCRs Gpr124 and Gpr125. Our preliminary data has shown loss of Remo in astrocytes results in a failure of neurite refinement in a specific subclass of neurons, termed Beat-VaM neurons, which undergo local pruning (i.e. elimination of axon/dendrites and synapses followed by regrowth of the pruned parent neuron). In Aim 1 I will perform a detailed genetic analysis of Remo in the activation of pruning and elimination of neuronal debris in Beat-VaM neurons. In Aim 2, by examining live and fixed tissue samples, I will define the precise role for Remo in the transformation of astrocytes into phagocytes, recognition, internalization and processing of neural debris for elimination; and define the localization of Remo throughout this process. Finally, in Aim 3, I will explore the role of Remo in other glial phagocytic events, including remodeling of other neurons during development, or after axonal injury (i.e. axotomy). Together, these studies will provide exciting new insight into the mechanisms by which glia help activate and execute neuronal remodeling and responses to injury in vivo. My goals as a postdoctoral fellow are to a) develop technical and intellectual approaches needed to start my own independent research lab studying neurodevelopment and b) learn the tools and techniques needed to utilize Drosophila to understand the contributions of glia to neurodevelopment in deep molecular terms. My proposed work has excellent training potential—I will learn a new genetic model system, become an expert in neurodevelopmental studies in Drosophila, and learn cutting edge imaging and genome engineering approaches for use with this system. The additional training activities proposed during my fellowship will also enhance my quantitative and analytical skills, improve my ability to communicate my work, and engage in effective mentorship. Collelectively, this fellowship will help prepare me to successfully transition towards a career as an independent investigator.
