title: DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris.
abstract: Nervous system injury or disease leads to activation of glia, which govern postinjury responses in the nervous system. Axonal injury in Drosophila results in transcriptional up-regulation of the glial engulfment receptor Draper; there is extension of glial membranes to the injury site (termed activation), and then axonal debris is internalized and degraded. Loss of the small GTPase Rac1 from glia completely suppresses glial responses to injury, but upstream activators remain poorly defined. Loss of the Rac guanine nucleotide exchange factor (GEF) Crk/myoblast city (Mbc)/dCed-12 has no effect on glial activation, but blocks internalization and degradation of debris. Here we show that the signaling molecules downstream of receptor kinase (DRK) and daughter of sevenless (DOS) (mammalian homologs, Grb2 and Gab2, respectively) and the GEF son of sevenless (SOS) (mammalian homolog, mSOS) are required for efficient activation of glia after axotomy and internalization/degradation of axonal debris. At the earliest steps of glial activation, DRK/DOS/SOS function in a partially redundant manner with Crk/Mbc/dCed-12, with blockade of both complexes strongly suppressing all glial responses, similar to loss of Rac1. This work identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glial responses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris.
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Tsai-Yi
authors.initials: TY
authors.lastname: Lu
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Johnna
authors.initials: J
authors.lastname: Doherty
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605 marc.freeman@umassmed.edu.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D017344:Genes, Insect; D009154:Mutation; D009410:Nerve Degeneration; D009457:Neuroglia / Q000502:physiology*; D010588:Phagosomes / Q000502:physiology; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics / Q000502:physiology; D020839:Son of Sevenless Protein, Drosophila / Q000235:genetics / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C521975:Ced-12 protein, Drosophila; D003598:Cytoskeletal Proteins; C100319:Dos protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D050737:Proto-Oncogene Proteins c-crk; C090146:Rac1 protein, Drosophila; D020839:Son of Sevenless Protein, Drosophila; C080530:drk protein, Drosophila; C107441:mbc protein, Drosophila; D020744:rac GTP-Binding Proteins; D018631:ras Proteins
keywords: Draper pathway; Wallerian degeneration; engulfment signaling; reactive glia
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