Intrinsic mechanisms for axon regeneration: insights from injured axons in Drosophila

Abstract

Axonal damage and loss are common and negative consequences of neuronal injuries, and also occur in some neurodegenerative diseases. For neurons to have a chance to repair their connections, they need to survive the damage, initiate new axonal growth, and ultimately establish new synaptic connections. This review discusses how recent work in Drosophila models have informed our understanding of the cellular pathways used by neurons to respond to axonal injuries. Similarly to mammalian neurons, Drosophila neurons appear to be more limited in their capacity regrow (regenerate) damaged axons in the central nervous system, but can undergo axonal regeneration to varying extents in the peripheral nervous system. Conserved cellular pathways are activated by axonal injury via mechanisms that are specific to axons but not dendrites, and new unanticipated inhibitors of axon regeneration can be identified via genetic screening. These findings, made predominantly via genetic and live imaging methods in Drosophila, emphasize the utility of this model organism for the identification and study of basic cellular mechanisms used for neuronal repair.

Figure 1. Axons regenerate to varying extents in different Drosophila axon injury models

New axonal growth after injury, cartooned in pink, occurs to varying degrees after injuries in the adult and larval PNS. Some of the sensory neurons that line the larval body wall initiate remarkable regeneration along the original path of the lost axon [10]. Other injury models in the adult wing and larval peripheral nerves note extensive new axonal sprouting [29,54]. This undirected growth (‘sprouting’) may reflect an absence of salient cues to guide directed growth for the regenerating axon. In some cases, sensory neurons in the adult wing can initiate extensive directed growth, however this occurs along a new path that is distinct (‘misrouted’) from the original path [54]. This may be a side effect of massive tissue damage and scar formation at the injury site that prevents the axon from finding its correct path. In contrast to the PNS injuries, the two studies thus far that have injured axons in the CNS have noted very poor growth responses [10,11]. The contrast is particularly interesting for the Class IV da sensory neuron axons, since the axons grow robustly after injury in a PNS location but very poorly after injury in a CNS location [10,44].

Figure 2. Injury triggered microtubule dynamics in neurons

Microtubules are organized in axons and dendrites with distinct orientations of their growing (plus) ends: in axons microtubules orient with plus ends facing away from the cell body (plus-end-out), colored green, while in dendrites microtubules orient with minus-ends-out, colored red. Axonal injury, but not dendritic injury, triggers a global increase in the number of growing microtubules. In contrast, increased microtubule is observed in distal dendrite stump, but not distal axon stump. Mixed-polarity microtubules are observed in both proximal axon stump and dendrite stump. ER and microtubules are accumulated in growing axon tips, but not in growing dendrite tips, 96 hours after axotomy (for class I da neuron). In the case of complete axonal removal, one dendrite can switch microtubule polarity and become a growing axon.