AMP-Activated Protein Kinase Links Neuronal Remodeling to Metabolic Control

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Neuronal morphogenesis does not only involve progressive events like neurite outgrowth, but also regressive events like neurite degeneration, known as neuronal remodeling, or pruning. A well-suited model to study pruning mechanisms are Drosophila peripheral sensory neurons, which prune their larval dendrites at the onset of metamorphosis. This process is induced by ecdysone-dependent transcription and involves remodeling of the neuronal cytoskeleton to allow for neurite abscission and subsequent degeneration. Ecdysone is known to have strong effects also on cell growth and metabolism, but links between metabolism and pruning have not been assessed. We found that two members of the AMP-activated protein kinase family - Par-1/MARK and AMPK itself - are required for pruning. Whereas Par-1 is required for cytoskeletal remodeling, our genetic data for AMPK show that this kinase links cellular metabolism (translation and energy metabolism) to neuronal remodeling. Here, we propose to systematically investigate the interplay between cellular metabolism and neuronal remodeling. To this end, we will (1) use RNASeq and FRET-based metabolite reporters to describe the metabolic transitions of early pupal neurons; and (2) identify AMPK targets in genetic screens for modifiers of the AMPK pruning defect. AMPK targets will be confirmed biochemically in kinase assays. Furthermore, we have identified candidate AMPK upstream kinases and phosphatases We will confirm these biochemically and we will assess how these factors link AMPK to upstream ecdysone hormonal regulation. Our project will provide important insights into the interplay between metabolism and neuronal connectivity.