Draper Doppelganger

Science Signaling  08 May 2012:
Vol. 5, Issue 223, pp. ec127
DOI: 10.1126/scisignal.2003194

Glia respond to damaged neurons by extending membrane processes to phagocytose (or engulf) and clear cellular debris. In Drosophila, glial engulfment requires the engulfment receptor Draper and its downstream effectors, which includes the nonreceptor tyrosine kinase Shark. Logan et al. investigated the role of the three Draper isoforms in regulating engulfment. The intracellular ITAM (immunoreceptor tyrosine–based activation motif) of Draper I was required for the glial engulfment of debris from severed axons of olfactory receptor neurons (ORNs) in Drosophila. In contrast, Draper II inhibited the ability of glia to clear debris, an effect that required the ITIM (immunoreceptor tyrosine–based inhibitory motif) in the intracellular domain. In transfected cells, the tyrosine phosphatase Corkscrew (Csw) interacted with and dephosphorylated Draper II; in addition, Csw also dephosphorylated Shark, which would be expected to inhibit its activity. Overexpression of Draper II in glial cells prevented the clearance of axonal debris in vivo, an effect that was reduced by RNA interference (RNAi) directed against Csw in glial cells. After ORN injury, the mRNA abundance of Draper II increased more slowly than did that of Draper I, consistent with a role for Draper II in terminating engulfment responses mediated by Draper I. Flies expressing Csw-specific RNAi in glia showed higher abundance of Ced-6 (a protein involved in engulfing apoptotic cells) and of Draper I than did wild-type flies after antennal nerve axotomy (severing of the axon), suggesting that glial responses to the axotomy were not terminated in the absence of Csw. In a model of serial maxillary nerve axotomy, axonal debris was cleared in wild-type flies but not in flies expressing Csw-specific RNAi. The authors suggested that glial responses to repeated injury were inhibited in the absence of Csw and that Draper II and Csw serve to reset glia after an injury. These results show that Draper II and Csw act to terminate glial responses to neuronal damage by inhibiting the activity of Draper I. Draper III does not have a complete ITAM in its intracellular domain, and its absence did not affect glial engulfment.

M. A. Logan, R. Hackett, J. Doherty, A. Sheehan, S. D. Speese, M. R. Freeman, Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury. Nat. Neurosci. 15, 722–730 (2012). [PubMed]