Cellular and Molecular Mechanisms Underlying Neuronal Type-specific Axon Regeneration

Project description Failure in axon regeneration after nervous system lesion is a major roadblock for functional recovery. Axon regeneration is controlled by both intrinsic and extrinsic cues from both neurons and surrounding glial environment. However, our understanding of glial control of axon regeneration remains incomplete. Here, we investigate axon regeneration of well-defined sensory neurons in Drosophila larvae. This in vivo model offers a powerful opportunity to investigate axon regeneration with single-cell resolution and genetic tractability. Our pilot study has made novel findings by discovering a critical involvement of glia-neuron interactions, in the form of gliotransmission, in specifying axon regenerative differences of neuron types. Based on these findings, we hypothesize that gliotransmission orchestrates neuron type-specific axon regeneration. Specifically, we propose that axotomy activates Ca2+ signals in glial cells to elicit gliotransmission, leading to accumulation of extracellular ATP. ATP is then converted by ecto-5’- nucleotidases to adenosine before activating adenosine receptors in the select neuron type, resulting in neuron type-specific Ca2+ signals and axon regeneration. In this project, we will leverage the power of Drosophila genetics and combine it with multidisciplinary approaches to test this hypothesis. Because axon regeneration mechanisms are conserved, our findings will likely be relevant to other species including mammals.