Sci. STKE, 20 June 2006
NEUROBIOLOGY Clearing Damaged or Unneeded Axons
Three reports this week investigate the mechanisms by which excess axons are pruned during development to fine-tune synaptic connections and injured axons are cleared. Awasaki et al., MacDonald et al., and Hoopfer et al. investigated Drosophila axonal clearance. Awasaki et al. showed that axons of neurons in the mushroom body are removed during metamorphosis by recruitment of glia with processes that contain the draper and Ced-6 proteins. Ced-6 and draper, which is the fly homolog of the nematode Ced-1, are both involved in engulfment and removal of apoptotic cells. The neurons of the mushroom body do not undergo apoptosis; thus, a similar mechanism appears to mediate recognition of dying cells and neuronal processes destined for pruning during development. Draper mutant (drpr5) flies or flies expressing an RNAi in glia to suppress draper synthesis exhibited a lack of mushroom body neuron pruning and loss of infiltrating glia and glial engulfment activity. MacDonald et al. used the Drosophila olfactory system as the model to show that draper in glia was required for clearance of injured (transected) axons. Furthermore, transected axons underwent a process of Wallerian degeneration similar to that observed in mammals, because introduction of the mouse Wlds (a chimeric protein composed of nicotinamide mononucleotide adenylyltransferase and an E4 ubiquitin ligase) rescued transected axons from degeneration for weeks. Hoopfer et al. show that although Wlds rescues injured axons from degeneration, it does not prevent pruning of axons during development. Hoopfer et al. examined retinal ganglion cell (RGC) and cortical layer 5 pruning in wild-type and Wlds mice and found no difference in the remodeling that occurs during development. However, the Wlds mice showed delayed degeneration of RGC in response to transection. Hoopfer et al. found no effect of Wlds in Drosophila on the pruning of axons of the mushroom body and also reported that Wlds delayed degeneration of Drosophila olfactory neurons following transection. Awasaki et al. reported that ecdysone signaling was required for mushroom body pruning. A dominant-negative ecdysone receptor inhibited the increase in draper in the glia and the cytoskeletal disruption exhibited by the axons that were targeted for pruning. Hoopfer et al. showed that ecdysone signaling in the transected axons did not appear to be involved in their degeneration. The results from these three studies suggest that although the initiating events in axon pruning and degeneration are different, the mechanism by which glia recognize and remove these neuronal processes involve the same components, which are also common to the process by which apoptotic cells are recognized and eliminated. See Fainzilber and Twiss for a discussion of these articles and more about the Wlds mutation.
T. Awasaki, R. Tatsumi, K. Takahashi, K. Arai, Y. Nakanishi, R. Ueda, K. Ito, Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis. Neuron 50, 855-867 (2006). [Online Journal]
J. M. MacDonald, M. G. Beach, E. Porpiglia, A. E. Sheehan, R. J. Watts, M. R. Freeman, The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron 50, 869-881 (2006). [Online Journal]
E. D. Hoopfer, T. McLaughlin, R. J. Watts, O. Schuldiner, D. D. M. O'Leary, L. Luo, Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning. Neuron 50, 883-895 (2006). [Online Journal]
M. Fainzilber, J. L. Twiss, Tracking in the Wlds: The hunting of the SIRT and the luring of the Draper. Neuron 50, 819-821 (2006). [Online Journal]
Citation: Clearing Damaged or Unneeded Axons. Sci. STKE 2006, tw204 (2006).
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