Interdisciplinary Graduate Program
Department of Neurobiology; Freeman Lab; Graduate School of Biomedical Sciences, Neuroscience Program; Graduate School of Biomedical Sciences, Interdisciplinary Graduate Program
Molecular and Cellular Neuroscience
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-12has 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 glialresponses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris.
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Citation: Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12544-9. doi: 10.1073/pnas.1403450111. Epub 2014 Aug 6. Link to article on publisher's website
Draper pathway, Wallerian degeneration, engulfment signaling, reactive glia
Proceedings of the National Academy of Sciences of the United States of America
Lu, Tsai-yi; Doherty, Johnna E.; and Freeman, Marc R., "DRK/DOS/SOS Converge with Crk/Mbc/dCed-12 to Activate Rac1 during Glial Engulfment of Axonal Debris" (2014). GSBS Student Publications. 1864.