Dissecting the mechanisms by which the chemokine-like Orion induces axon-bundle glia infiltration and phagocytosis during developmental neurodegeneration – ExOrion

Nervous systems are initially overpopulated with neurons. This is followed by a key period of remodeling whereby a subset of inappropriate neurons is removed to optimize function in the adult nervous system. The selection of specific connections for elimination involves an exclusive communication between neurons and phagocytic glia. Recently we identify the Drosophila chemokine-like Orion as a novel secreted protein with essential functions in this dialog using mushroom bodies (MB)s as an in vivo model. MBs gamma axons are organized in bundles, fated to selective degeneration, where astrocytes infiltrate and phagocyte neuronal varicosities. In our recent studies we demonstrated that upon orion knockdown, astrocyte infiltration into MBs was blocked. Our new data suggest that Orion trapped at the plasma membrane is sufficient for glia MB-infiltration and engulfment but that phagocytosis requires exosome-carried Orion. Taken together, our publications and preliminary data suggest that Orion is likely secreted in a finely regulated manner to ensure infiltration versus phagocytosis. Thus, we hypothesize that the way in which Orion, and chemokines in general, is presented to glia determines the response and behavior of these cells. Using a combination of neurogenetics, biochemical, cellular and in vivo studies, the proposed consortium will address the following aims:
1/ to uncover the intracellular machinery required for Orion secretion by MB neurons.
2/ to characterize the topological organization of Orion after its release.
3/ to decipher glial cell signaling pathways activated by Orion.
By providing insights on how Orion is trafficked and secreted, presented to glial cells, and how it controls specific transcriptional programs required for glia infiltration and phagocytosis, this project could lead to unprecedent improvements in the understanding of the role of glia in developmental and pathological neurodegeneration.