What might be the logic for incorporating a selleck chemical glial cell in the induction of prodegenerative signaling? A likely explanation is that by partitioning the prodegenerative-signaling system between two cells, additional layers of control can be imposed on the system so that errant activation of degeneration is unlikely. For example TNF-α activating enzyme (TACE) is required to cleave TNF-α prior to secretion and represents an essential

form of regulation that may be required in glia. In addition full activation of the degenerative response might include active insertion of the TNFR in the membrane by the motoneuron. This organization would restrict the spread of prodegenerative signaling such that only motoneurons that have been stressed and have actively inserted TNFR in the membrane will respond to

TNF-α released from the glial cell and degenerate. This possibility remains to be tested. Here, we demonstrate that peripheral glial cells that surround motor axons express Eiger. Because Eiger knockdown in these cells is sufficient to suppress degeneration after INK1197 price an axonal insult, we conclude that Eiger has the potential to activate prodegenerative signaling via the Wengen receptor along the length of the motor axons, as diagrammed in Figure 9. However, it remains unknown how this prodegenerative signaling spreads to drive the degeneration of the presynaptic nerve terminal at the NMJ because glial ensheathment of motor axons stops prior to the NMJ (Figure 1). One possibility is that dynamic invasion of the NMJ by peripheral glia conveys prodegenerative signaling to this site (Fuentes-Medel et al., 2009). Another possibility is

that caspases, once activated in the axon, can be mobilized to the presynaptic terminal of the NMJ. This possibility Histamine H2 receptor is consistent with the catalytic activity of caspases and our demonstration of caspase mobility within motor axons (Figure 7C). Ultimately, the mechanisms that disseminate prodegenerative signaling throughout a cell are not well understood. Likewise, it is not understood how prodegenerative signaling responsible for selective dendrite pruning is restricted to specific neuronal compartments. Finally, it is worth emphasizing that many of the prodegenerative-signaling molecules identified in our study do not adversely effect neuromuscular development when mutated or deleted. For example mutations in eiger, dcp-1, debcl, and dark show no obvious NMJ phenotype in larval stages and are homozygous viable as adult flies. Thus, the neuroprotective effects of these loss-of-function mutations can be separated from the molecular mechanisms of motoneuron growth control.