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Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling

Nature volume 453, pages 935–939 (2008)Cite this article

Abstract

The cellular machinery promoting phagocytosis of corpses of apoptotic cells is well conserved from worms to mammals. An important component is the Caenorhabditis elegans engulfment receptor CED-1 (ref. 1) and its Drosophila orthologue, Draper2. The CED-1/Draper signalling pathway is also essential for the phagocytosis of other types of ‘modified self’ including necrotic cells3, developmentally pruned axons4,5 and dendrites6, and axons undergoing Wallerian degeneration7. Here we show that Drosophila Shark, a non-receptor tyrosine kinase similar to mammalian Syk and Zap-70, binds Draper through an immunoreceptor tyrosine-based activation motif (ITAM) in the Draper intracellular domain. We show that Shark activity is essential for Draper-mediated signalling events in vivo, including the recruitment of glial membranes to severed axons and the phagocytosis of axonal debris and neuronal cell corpses by glia. We also show that the Src family kinase (SFK) Src42A can markedly increase Draper phosphorylation and is essential for glial phagocytic activity. We propose that ligand-dependent Draper receptor activation initiates the Src42A-dependent tyrosine phosphorylation of Draper, the association of Shark and the activation of the Draper pathway. These Draper–Src42A–Shark interactions are strikingly similar to mammalian immunoreceptor–SFK–Syk signalling events in mammalian myeloid and lymphoid cells8,9. Thus, Draper seems to be an ancient immunoreceptor with an extracellular domain tuned to modified self, and an intracellular domain promoting phagocytosis through an ITAM-domain–SFK–Syk-mediated signalling cascade.

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Figure 1: Shark binds an ITAM in the Draper intracellular domain.
Figure 2: Shark is required for recruitment of Draper and glial membranes to severed axons.
Figure 3: Shark is required for glial clearance of severed axons from the CNS.
Figure 4: Src42Aa is required for glial responses to axon injury and modulates Draper phosphorylation status.

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Acknowledgements

This work was supported by National Institutes of Health grants (1R01NS053538 to M.R.F., and 1RO1GM55293 and 1RO1CA26504 to E.R.S.), by an Albert Einstein Cancer Center Grant (PO3-13330 to E.R.S.), a Smith Family New Investigator Award (to M.R.F.) from the Smith Family Foundation, and a grant from the Christopher and Dana Reeves Foundation (to M.R.F.). M.R.F. is an Alfred P. Sloan Research Fellow.

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Author notes

  1. Jennifer S. Ziegenfuss and Romi Biswas: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605-2324, USA,

    Jennifer S. Ziegenfuss, Michelle A. Avery, Amy E. Sheehan & Marc R. Freeman

  2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA,

    Romi Biswas, Kyoungja Hong, Yee-Guide Yeung & E. Richard Stanley

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Correspondence to E. Richard Stanley or Marc R. Freeman.

Supplementary information

Supplementary information

The file contains Supplementary Figure 1 showing RNAi knockdown of Src64B or Btk29A does not affect glial responses to axon injury or clearance of severed axons from the CNS. These experiments show that RNAi knockdown in glia of Src64b or btk29A, the only other Src kinases in Drosophila besides Src42a, do not affect glial responses to axonal injury, nor the ability of glia to phagocytose degenerating axonal debris. (PDF 3080 kb)

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Ziegenfuss, J., Biswas, R., Avery, M. et al. Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature 453, 935–939 (2008). https://doi.org/10.1038/nature06901

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