Glia continuously survey neuronal health during development, providing trophic support to healthy neurons while rapidly engulfing dying ones. These diametrically-opposed functions necessitate a foolproof mechanism enabling glia to unambiguously identify those neurons to support versus those to engulf. To ensure specificity, glia are proposed to interact with dying neurons via a series of carefully choreographed steps. However, these crucial interactions are largely obscure. We present novel preliminary data that dying neurons and glia communicate via Toll receptor-regulated innate immune signaling. Neuronal apoptosis drives processing and activation of the Toll-6 ligand, Sptzle5 (Spz5). This cue activates a dSARM-mediated Toll-6 transcriptional pathway in glia, which controls expression of the Draper engulfment receptor. Our results identify an upstream priming signal that prepares glia for phagocytosis. Thus, a core innate immune pathway plays an unprecedented role setting the valence of neuron-glia interactions during development. The identification of this non-canonical and previously unexplored pathway raises fundamental questions about its signaling mechanism, which we address in this proposal. First, we will define the mechanism of action of dSARM by rigorously testing its biochemical requirements in the pathway. Second, we will establish the regulation and function of Spz5 in dying neurons. Together, these experiments will define an entirely new molecular mechanism regulating interactions between dying neurons and glial phagocytes. By defining this cascade, we open the door to a systematic understanding of this innate immune pathway in neuron-glia interactions in development.
This study will define the function of an evolutionarily-conserved innate immune signaling pathway in the developing brain. Outside the nervous system, innate immune pathways are required for pathogen recognition and engulfment. We find that one such pathway has been repurposed in the nervous system where it mediates signaling between dying neurons and phagocytic glia. By establishing how the dying neuron sends the distress signal, and the glial cell responds to it, this work builds a foundation for determining how the nervous system eliminates extra cells during development and in disease states.
