Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk.

Scheib JL, Sullivan CS, Carter BD
J Neurosci. 2012 32 (38): 13022-31

PMID: 22993420 · PMCID: PMC3464495 · DOI:10.1523/JNEUROSCI.6350-11.2012

During the development of the peripheral nervous system there is extensive apoptosis, and these neuronal corpses need to be cleared to prevent an inflammatory response. Recently, Jedi-1 and MEGF10, both expressed in glial precursor cells, were identified in mouse as having an essential role in this phagocytosis (Wu et al., 2009); however, the mechanisms by which they promote engulfment remained unknown. Both Jedi-1 and MEGF10 are homologous to the Drosophila melanogaster receptor Draper, which mediates engulfment through activation of the tyrosine kinase Shark. Here, we identify Syk, the mammalian homolog of Shark, as a signal transducer for both Jedi-1 and MEGF10. Syk interacted with each receptor independently through the immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular domains. The interaction was enhanced by phosphorylation of the tyrosines in the ITAMs by Src family kinases (SFKs). Jedi association with Syk and activation of the kinase was also induced by exposure to dead cells. Expression of either Jedi-1 or MEGF10 in HeLa cells facilitated engulfment of carboxylated microspheres to a similar extent, and there was no additive effect when they were coexpressed. Mutation of the ITAM tyrosines of Jedi-1 and MEGF10 prevented engulfment. The SFK inhibitor PP2 or a selective Syk inhibitor (BAY 61-3606) also blocked engulfment. Similarly, in cocultures of glial precursors and dying sensory neurons from embryonic mice, addition of PP2 or knock down of endogenous Syk decreased the phagocytosis of apoptotic neurons. These results indicate that both Jedi-1 and MEGF10 can mediate phagocytosis independently through the recruitment of Syk.

MeSH Terms (35)

Amino Acid Motifs Animals Apoptosis Arabidopsis Proteins Cell Count Cells, Cultured Coculture Techniques Embryo, Mammalian Enzyme Inhibitors Female Ganglia, Spinal Gene Expression Regulation Green Fluorescent Proteins Humans Immunoprecipitation Immunoreceptor Tyrosine-Based Activation Motif Intracellular Signaling Peptides and Proteins Intramolecular Transferases Male Membrane Proteins Mice Microglia Mutagenesis, Site-Directed Mutation Neurons Niacinamide Phagocytosis Phosphorylation Protein-Tyrosine Kinases Pyrimidines RNA, Small Interfering Signal Transduction Staurosporine Syk Kinase Transfection

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