Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

Abstract

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. Here we show that dying neurons and glia communicate via Toll receptor-regulated innate immune signaling. Neuronal apoptosis drives processing and activation of the Toll-6 ligand, Spätzle5. This cue activates a dSARM-mediated Toll-6 transcriptional pathway in glia, which controls expression of the Draper engulfment receptor. Pathway loss drives early-onset neurodegeneration, underscoring its functional importance. 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. Dying neurons are proposed to interact with phagocytic glia via a series of carefully choreographed steps, but these signaling interactions are poorly understood. McLaughlin et al. define a Toll receptor-mediated innate immune signaling pathway that acts to ensure the speed and specificity of neuronal corpse engulfment during neurodevelopment.