Abstract
Neuronal damage induced by injury, stroke, or neurodegenerative disease elicits swift immune responses from glial cells, including altered gene expression, directed migration to injury sites, and glial clearance of damaged neurons through phagocytic engulfment. Collectively, these responses hinder further cellular damage, but the mechanisms that underlie these important protective glial reactions are still unclear. Here, we show that the evolutionarily conserved trimeric protein phosphatase 4 (PP4) serine/threonine phosphatase complex is a novel set of factors required for proper glial responses to nerve injury in the adult Drosophila brain. Glial-specific knockdown of PP4 results in reduced recruitment of glia to severed axons and delayed glial clearance of degenerating axonal debris. We show that PP4 functions downstream of the the glial engulfment receptor Draper to drive glial morphogenesis through the guanine nucleotide exchange factor SOS and the Rho GTPase Rac1, revealing that PP4 molecularly couples Draper to Rac1-mediated cytoskeletal remodeling to ensure glial infiltration of injury sites and timely removal of damaged neurons from the CNS.
Highlights
Glial cells continuously survey the brain and respond swiftly to any form of stress or damage.[1]
We propose that phosphatase 4 (PP4) is a downstream effector of the glial receptor Draper and that it signals through the SOS guanine nucleotide exchange factors (GEFs) complex and the GTPase Rac[1] to promote proper glial membrane infiltration of injury sites and clearance of degenerating neuronal material
One day after maxillary nerve axotomy, we observed a significant increase in Draper on maxillary olfactory receptor neuron (ORN)-innervated glomeruli (Figures 2b and i), but this response was significantly attenuated in falafelRNAi, PP4cRNAi, and PP4r2RNAi animals (Figures 2d, f, h, and i Po0.0001), suggesting that the PP4 complex is essential for proper recruitment of Draper to severed nerves
Summary
Glial cells continuously survey the brain and respond swiftly to any form of stress or damage.[1] Acute insults, as well as chronic neurodegenerative conditions, trigger robust immune responses from glia.[2,3] Reactive glia undergo striking morphological changes and infiltrate injury sites to rapidly phagocytose cellular debris.[4,5] Glial changes in cell shape, size, and migration in response to neurodegeneration are highly conserved hallmark reactions to trauma in species ranging from Drosophila to humans. We propose that PP4 is a downstream effector of the glial receptor Draper and that it signals through the SOS GEF complex and the GTPase Rac[1] to promote proper glial membrane infiltration of injury sites and clearance of degenerating neuronal material
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