Insulin receptors are abundantly expressed in the central nervous system of invertebrates and vertebrates, although their roles have remained elusive. We have discovered a novel function for the Drosophila insulin receptor (DInr) in axon guidance in the visual system. We have shown that DInr function is necessary for photoreceptor cell (R cell) axon targeting from the retina to the brain to form a precise retinotopic map during development. DInr functions as a guidance receptor for the Dock pathway: DInr interacts directly with Dock, to link extracellular signals to axonal migration via activation of the downstream effector p21-activated kinase. This function of DInr is genetically independent of Chico, the Drosophila IRS homolog. Our findings suggest a general role for the insulin receptor family in axon guidance throughout the animal kingdom. In this application, we propose experiments to further elucidate the precise role of DInr in regulating axon guidance. We will carry out a detailed phenotypic characterization of abnormalities associated with loss of DInr function in R cells. Further, we will define the molecular basis for the interaction between DInr and Dock, an evolutionarily conserved SH2/SH3 domain adapter protein. These studies will allow us to distinguish the mechanisms utilized by DInr to regulate axon guidance through the Dock pathway and cell growth, thought to be mediated by a Chico-dependent pathway. Finally, we will initiate in vitro and in vivo studies to identify the ligand for DInr in regulating axon guidance. The receptor may respond to either attractive or repellent cues provided in the environment by one or more ligands to target R cells to their correct topographic locations in the developing brain. Our studies will have broad implications for understanding the function of insulin receptors in the brain and for elucidating mechanisms underlying neuronal insulin receptor control of eating behavior, learning and memory.
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