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


Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: [Email]


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 the 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.


Draper,FoxO,Furin,SARM1,Spätzle,Toll,find-me signal,glia,neurodegeneration,phagocytosis,

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