Jedi-1 and MEGF10 Signal Engulfment of Apoptotic Neurons through the Tyrosine Kinase Syk

Abstract

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 co-expressed. 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 co-cultures 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.

DrosophilaCentral Nervous System Glia

“…Work on Drosophila Draper represents a good example of how basic cellular mechanisms can be elucidated in Drosophila glia and will teach us about mammalian glial cell biology. Recent work has shown that DRG satellite cells also use MEGF10/Jedi signaling (the mammalian orthologs of Draper/CED-1) to engulf cell corpses during mammalian nervous system development (Wu et al 2009), and that MEGF10 also activates an Src family signaling cascade similar to Src42a and Shark (Scheib et al 2012). Moreover, Chung et al (2013) recently discovered an exciting and conserved role for MEGF10 in astrocyte engulfment of synapses during neural circuit refinement in the mammalian visual system (Chung et al 2013).…”

Caveolin-1–mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype

“…Src family kinases (SFKs) are cytosolic nonreceptor tyrosine kinases that promote microglia activation triggered by different inflammatory stimuli (45)(46)(47)(48)(49)(50). Classical microglial stimulation with LPS increases the activity of SFKs, including the prototypical and founding member c-Src (36,51).…”

Defective Phagocytic Corpse Processing Results in Neurodegeneration and Can Be Rescued by TORC1 Activation

“…Specifically, we looked for the presence of pyknotic nuclei, highly condensed chromatin suggestive of dead cells (Savill et al, 2002). We dissected brains from 1-d-old …”

“…Drosophila melanogaster has been a powerful model for understanding glia-dependent phagocytosis and neurodegenerative diseases (Shulman et al, 2003;Fullard et al, 2009). The CED-1 ortholog Draper (Drpr) is an important recognition receptor for glia-dependent phagocytosis .…”