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. Author manuscript; available in PMC: 2015 Jan 30.
Published in final edited form as: Cell Rep. 2014 Jan 9;6(2):247–253. doi: 10.1016/j.celrep.2013.12.022

Dendrite injury triggers DLK-independent regeneration

Michelle C Stone 1, Richard M Albertson 1, Li Chen 1, Melissa M Rolls 1
PMCID: PMC3954604  NIHMSID: NIHMS551149  PMID: 24412365

Summary

Axon injury triggers regeneration through activation of a conserved kinase cascade that includes the dual leucine zipper kinase (DLK). While dendrites are damaged during stroke, traumatic brain injury and seizure, it is not known whether mature neurons monitor dendrite injury and initiate regeneration. We probed the response to dendrite damage using model Drosophila neurons. Two larval neuron types regrew dendrites in distinct ways after all dendrites were removed. Dendrite regeneration was also triggered by injury in adults. We next tested whether dendrite injury was initiated with the same machinery as axon injury. Surprisingly, DLK, JNK and fos were dispensable for dendrite regeneration. Moreover, this MAP kinase pathway was not activated by injury to dendrites. Thus neurons respond to dendrite damage and initiate regeneration without using the conserved DLK cascade that triggers axon regeneration.

Introduction

Most neurons need both dendrites and axons to function. The responses of neurons to axon injury are relatively well documented. After severe axon damage, distal regions of axons are cleared by Wallerian degeneration (Coleman and Freeman, 2010; Wang et al., 2012), which is followed by reinitiation of axon outgrowth. In mammals, both degeneration and regeneration are more efficient in peripheral than central neurons (Huebner and Strittmatter, 2009; Liu et al., 2011; Vargas and Barres, 2007). Axon injury triggers a cascade of signals that travel back from the injury site to the cell body. Within minutes of the initial trauma, a calcium wave travels back to the cell body (Cho and Cavalli, 2012; Ghosh-Roy et al., 2010). Subsequently, microtubule motor-based transport brings signaling molecules between the site of injury and the cell body (Abe and Cavalli, 2008; Rishal and Fainzilber, 2010). This process may take hours to days depending on the distance from the site of injury to the cell body. Several key proteins take this motor-based route. Among these, the mitogen-activated protein kinase kinase kinase (MAPKKK) dual leucine zipper kinase (DLK) has been shown to be required for efficient regeneration in worms, flies and mammals (Hammarlund et al., 2009; Shin et al., 2012; Xiong et al., 2010; Yan et al., 2009), and thus seems to be a core signaling element in the response to axon injury. A major transcriptional response is mounted downstream of DLK to allow reinitiation of axon growth from the damaged cell.

While key players in axon regeneration have been identified, it is not known whether neurons have signaling machinery that senses dendrite damage, or if mature neurons can regenerate dendrites. Dendrites are particularly susceptible to damage by excitotoxicity and other environmental changes during stroke, seizure and traumatic brain injury (Gao and Chen, 2011; Greenwood and Connolly, 2007; Murphy et al., 2008; Risher et al., 2010; Zeng et al., 2007). It is difficult to track dendrites from individual cells in mammals over time, so it has not been possible to determine whether dendrite regeneration is possible after damage using these models. Therefore several labs have turned to Drosophila dendritic arborization neurons to ask whether dendrite injury triggers regeneration.

Dendritic arborization (da) neurons in Drosophila larvae are highly polarized cells with dendrites that innervate the body wall and axons that extend to the CNS (Grueber et al., 2002). While their dendrites are sensory, they share many features with dendrites that house postsynaptic sites. For example, minus-end-out microtubules are present in dendrites, but not axons, of all types of mammalian and Drosophila neurons examined, including da neurons (Baas and Lin, 2011; Stone et al., 2008).

Different types of da neurons exist in Drosophila larvae, and they can be distinguished by arbor complexity and tiling behavior (Grueber et al., 2002). Several studies have suggested that the most complex of these neurons, the class IV cells, have some capacity to respond to dendrite damage, although this becomes more limited as larvae age (Song et al., 2012; Sugimura et al., 2003). These studies also agree that the simplest da neurons, the class I cells, are unable to reinitiate growth in response to dendrite injury at any point during larval life, and can only do this during embryogenesis. Loss of sensory endings in zebrafish skin also triggers robust reinnervation only very early in development (O'Brien et al., 2009). Thus the evidence so far suggests that, even in the peripheral nervous system where regeneration tends to be most exuberant, only some cells early in development can upregulate dendrite growth in response to injury. However, all studies on responses of single cells to dendrite injury have damaged only one dendrite. To fully test the idea that only subsets of neurons at specific developmental stages can initiate dendrite regeneration, we developed methods to remove all dendrites from neurons and reasoned that the cells would either die or regenerate.

Results

Dendrite injury triggers robust regeneration in multiple types of dendritic arborization neurons

To test the idea that only subsets of neurons at specific developmental stages can initiate dendrite regeneration, we developed methods to remove all dendrites from da neurons and reasoned that the cells would either die or regenerate. The simplest da neurons, including the ddaE cell, normally have very stable dendrite arbors during larval life and do not add or remove branches (Figure 1A, 1D and (Sugimura et al., 2003)). We thus tested whether these neurons would die if all dendrites were removed. We severed all dendrites from larval ddaE neurons in whole animals with a pulsed UV laser. After dendrite removal, larvae were returned to food. We imaged the cells at 5h to make sure dendrites were completely severed, and then on subsequent days to determine if the cells would die. At 24h after injury, the cells were still alive. Moreover in most cases new processes could be seen to emerge from the cell body. By 48h a branched dendrite arbor was visible in almost half (16/34) of the animals tested (Figure 1B and S1A). The remaining neurons grew fine processes alongside the axon (Figure S1B). We speculate that in neurons with peri-axonal growth, the new processes could not reach the layer in which they normally arborize, which is between the epidermal cells and basement membrane (Kim et al., 2012); in many of them the cell body was seen to float deeper into the animal after the dendrites were cut. The remaining analysis will focus only on the cells that regrew processes into the region normally occupied by dendrites rather than along the axon. At 96h after dendrite injury, the area of the body wall covered by the new processes was smaller than in cells without injury. However, when we counted dendrite branch points, we found that the complexity had reached a similar level to that before injury (Figure 1E). These neurons, which are part of a circuit that is responsible for coordinated motion (Hughes and Thomas, 2007), and do not normally tile the entire body wall (Grueber et al., 2002) perhaps rely more on complexity of the arbor rather than exact area of coverage to function. We conclude that the ddaE neuron can regenerate a branched arbor after dendrite removal, and that it regrows to the same branching complexity as uninjured neurons.

Figure 1. Dendrites regrow completely after they are removed from larval neurons.

Figure 1

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A. An example of an uninjured ddaE neuron expressing mCD8-GFP and tracked during four days of larval life is shown. B. A ddaE neuron expressing mCD8-GFP had all dendrites removed at their base (arrows) and was then tracked for four days. At 5h the cut dendrites have degenerated. C. A ddaC neuron had its dendrites removed (arrows) and was then imaged over four days. 4h after dendrite severing degenerating remnants are seen. At 48h new dendrites do not reach the edge of the normal territory (double arrows). By 96h the new dendrites directly abut neighboring cells. D and E. Quantitation of branch point number in uninjured (D) ddaE neurons, and ddaE neurons after dendrite removal (E). Averages from 9 cells are shown in D and 7 (5h and 96h) or 8 (0h and 48h) cells in E. related to S1

To test whether other cell types could respond to dendrite damage by growing new processes, we performed dendrite removal on the class IV neuron ddaC. Class IV neurons tile the entire body wall (Grueber et al., 2002) and receive information about painful stimuli (Hwang et al., 2007). After dendrite removal, new processes initiated growth by 24h. At 48h after injury an elaborate arbor covered the central part of the ddaC territory (Figure 1C). By 96h after injury the entire territory was covered (Figure 1C). Out of 27 neurons tested all except 2 followed this pattern (pooled data from all genotypes used, Figure S1C). Thus, unlike the ddaE neuron, the ddaC neuron regenerated to cover its complete territory.

To determine whether the regrown processes were correctly specified as dendrites, we analyzed microtubule polarity in the new neurites that emerged after dendrite removal. The presence of minus-end-out microtubules distinguishes dendrites from axons in Drosophila, C. elegans and mammalian neurons (Baas et al., 1988; Goodwin et al., 2012; Stone et al., 2008), and is a good indicator of compartment identity. The new processes that formed after dendrite removal in the ddaC neuron initially had slightly mixed polarity. By 48h after injury, this had resolved to about 90% minus-end-out microtubules, similar to uninjured ddaC neurons (Figure S1D). This result suggests that the new processes are dendrites, and is in sharp contrast to dendrite growth initiated by damage to the proximal axon. In both mammals (Gomis-Ruth et al., 2008) and flies (Stone et al., 2010) proximal axotomy causes a new axon to grow from a dendrite. However, this new axon is easily distinguished from the processes that regrow after dendrite injury; it leaves the normal territory of the dendrites, is unbranched, and has plus-end-out microtubule polarity (Stone et al., 2010). To further test the identity of the regrown processes, we used two additional methods. First, we used a marker, Apc2-GFP, that localizes to dendrite branch points, the proximal axon, but not more distal regions of the axon (Rolls et al., 2007; Stone et al., 2010). This marker was expressed in ddaC neurons, and analyzed after dendrite removal. Both 48h and 96h after dendrite removal, it could be seen to occupy branch points in regrown processes, again suggesting these are specified as dendrites (Figure S1E). Second, we tested the effect of dynein on dendrite regrowth. Dynein is known to be required for dendrite development, and ddaC neurons in which it is reduced generate short, bushy arbors (Satoh et al., 2008; Zheng et al., 2008). In fact, because of the arrangement of microtubules in Drosophila neurons, it is predicted to be required for the bulk of transport from the cell body into dendrites (Rolls, 2011). Consistent with a role for dynein in transporting building blocks for dendrites, but not axons, axonal regeneration proceeded normally when dynein was reduced by RNAi (Figure S1F). Dendrite regrowth after removal initiated normally, but dendrite arbors were small and bushy (Figure S1F), recapitulating the phenotype observed during dendrite development (Satoh et al., 2008; Zheng et al., 2008). Thus several different lines of evidence suggest that the processes that regrow after dendrite removal are correctly specified as dendrites.

As previous studies have suggested that larval neurons have limited capacity to regenerate dendrites after a single dendritic injury (Song et al., 2012; Stone et al., 2010; Sugimura et al., 2003), we removed single dendrites from the ddaE and ddaC neurons. In analyzing the results we kept in mind that after total dendrite removal the ddaE neuron regenerated a dendrite arbor with similar complexity, but not coverage, to control arbors, and the ddaC neuron regenerated to cover the body wall. We therefore analyzed number of branch points for ddaE and visually scored coverage for ddaC (Figure S2A and B). Using this perspective, we found that removal of a single dendrite triggered a similar response in both cells to removal of all dendrites, that is the ddaC neuron regrew until its territory was covered, and the ddaE neuron added branch points to its remaining dendrite until complexity was regained. We also tested whether the position of the injury might affect the outcome and severed some dendrites further from the cell body. Again, we observed robust regrowth (Figure S2C).

Late larval and adult neurons retain the capacity to regrow dendrites

Previous studies suggested that the capacity of neurons to respond to dendrite damage decreases during larval life (Song et al., 2012; Sugimura et al., 2003). We therefore aged larvae longer than in the published studies and tested whether neurons could still respond to dendrite injury. We saw no difference in regenerative capacity between young and old larvae (Figure S2D). We conclude that dendrite injury triggers a robust regenerative growth response in larval Drosophila neurons irrespective of age, branching complexity, or whether one or all dendrites are removed.

The dendrite arbors of ddaE and ddaC function during larval life and so are, at least in this sense, mature. During pupariation, dendrites from both neurons are pruned and new arbors are regrown into the adult body wall. ddaC and other class IV neurons, including v’ada, persist through adult life, while ddaE undergoes apoptosis 3–5 days after adults emerge (Shimono et al., 2009). To address the possibility that larval neurons have some dendrite growth potential not present in adult neurons, we tested whether dendrite removal in adults could also trigger regenerative growth. We developed methods to mount living young adult flies so that we could sever dendrites in intact animals. We chose to use the most anterior v’ada neuron for these experiments as it could be visualized in the abdomen using the ppk-Gal4 driver with relatively little overlap from dendrites of other neurons.

As in larval neurons, we severed a major dendrite near its base and determined whether the cell would undergo apoptosis or would reinitiate dendrite outgrowth. We could not repeatedly remount the same adult for imaging, therefore we analyzed different cells at various times after injury. At 48h after dendrite removal 5/6 neurons had new processes sprouting near the cell body (Figure 2). At 96h or 120h after injury 12/13 neurons had regrown complex, branched arbors into their normal territory (Figure 2). Thus adult neurons seem to retain the capacity to respond to dendrite injury and to regenerate dendrites.

Figure 2. Adult neurons reinitiate dendrite outgrowth after dendrite injury.

Figure 2

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The major dendrite root in the anterior v’ada neuron in the adult abdomen was severed with a laser at 0h (except in top row). Flies were then returned to food vials and aged for 2, 4 or 5 days. They were then remounted and the same neuron was imaged. In all cases the cell remained alive and new dendrites had sprouted.

The conserved DLK axon regeneration pathway is not involved in the response to dendrite injury

In C. elegans, Drosophila and mammals, efficient axon regeneration requires signaling through the dual leucine zipper kinase (DLK, or Wallenda (wnd) in flies) pathway (Hammarlund et al., 2009; Shin et al., 2012; Xiong et al., 2010; Yan et al., 2009). DLK is a mitogen-activated protein kinase kinase kinase (MAPKKK) that initiates a signal transduction cascade after axon injury that includes cJun N-terminal kinase (JNK) in flies (Xiong et al., 2010), and both JNK and the related MAPK, p38, in C. elegans (Nix et al., 2011). In Drosophila, the AP-1 transcription factor fos is required for the transcriptional response to axon injury downstream of DLK (Xiong et al., 2010), and in mammals accumulation of the AP-1 transcription factor jun in the nucleus after axon injury requires DLK (Shin et al., 2012). Thus DLK is believed to be at the core of a conserved signaling cascade that initiates the cell body response to axon injury.

To determine whether dendrite regeneration requires this conserved injury signaling pathway, we used RNAi and mutant approaches to lower levels of DLK and assayed dendrite regeneration after complete dendrite removal in ddaC. As a control for the effectiveness of the RNAi in the ddaC neuron, we assayed axon regeneration. In control ddaC neurons, 7/7 axons initiated regeneration from the axon stump (Figure 3A and D). In contrast, only 1/8 of the wnd (DLK) RNAi neurons or 1/9 of the wnd1/wnd3 loss of function (Collins et al., 2006) mutants showed any sign of axon outgrowth (Figure 3B and D). Thus wnd reduction effectively blocked axon injury signaling in the ddaC neuron. We then tested dendrite regeneration in the same genetic backgrounds. The ddaC neurons with reduced wnd regrew dendrite arbors with similar efficiency and timing to control neurons (Figure 3C and D and S3A). We also tested whether wnd was required for dendrite regeneration in ddaE neurons, and again found that dendrite regeneration was robust when wnd was targeted by RNAi (Figure S3B). This result suggests DLK signaling is not required for dendrite regeneration. In the response to axon injury, DLK levels increase due to reduction in turnover by the ubiquitin ligase highwire (hiw) (Xiong et al., 2010). Hiw also seems to regulate DLK during dendrite development (Wang et al., 2013). However, like DLK, reduction of hiw impaired the response to axon injury, but not dendrite injury (Figure S3D).

Figure 3. Wnd is not required for dendrite regeneration.

Figure 3

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Axons (A and B) or dendrites (C) of ddaC neurons were severed at 0h. Larvae were remounted for imaging 4–5 hours later to check for complete severing and then at 48h and 96h to assay regeneration. Quantitation is shown in D. For axon injury, cells that were scored as regrowing extended axon stumps as shown in A, and cells that were scored as not regrowing retained a clear stump as in B. For dendrite injury, regrowing cells all had robust dendrite arbors as in C.

In Drosophila, downstream components of the DLK pathway include the kinase JNK (called bsk in flies), and the AP-1 transcription factor fos. Dominant negative forms of JNK (bskDN) or fos (fosDN) block the response to axon injury in motor neurons (Xiong et al., 2010) and block axon regeneration in dendritic arborization neurons ((Stone et al., 2010) and not shown). We therefore expressed both of these transgenes in the ddaC and ddaE neurons. In both genetic backgrounds in both cell types cases, dendrites regrew in the majority of neurons (Figure 4). Thus downstream components of the axon injury signaling pathway do not seem to be required for dendrite regeneration.

Figure 4. Downstream components of the DLK pathway are dispensable for dendrite regeneration.

Figure 4

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Examples of ddaC (A) and ddaE (B) neurons expressing bskDN and fosDN are shown at different times after dendrite removal. Arrows indicate sites of severing at 0h. C. ddaC cells were scored as regrowing dendrite arbors or not. All cells that regrew had robust arbors similar to those shown in A. D. Quantitation of branch point number in ddaE neurons after dendrite removal was performed as in Figure 1. The error bars show the standard deviation. The n’s are numbers of cells analyzed for each genotype at each timepoint following severing and are shown on the bars in the graph.

It is possible that although the DLK/JNK/fos pathway is not required for dendrite regeneration, it could be activated in parallel with another pathway that can compensate for its loss during the injury response. We therefore wished to use a reporter for pathway activation. JNK signaling is regulated in a negative feedback loop by MAP kinase phosphatases (MKPs) that are transcribed in response to activity of the pathway (Caunt and Keyse, 2012). After motor axon injury, levels of the MKP puckered (puc) can be seen to increase when monitored with a puc-βgal reporter (Xiong et al., 2010). We wished to use a puc reporter that could be visualized in whole, living animals, so we tested whether a puc-GFP protein trap (Morin et al., 2001) that reports on JNK signaling in embryos (Taniguchi et al., 2007) would increase in nuclear fluorescence after axon injury in the ddaE neuron. In uninjured ddaE neurons, low levels of puc-GFP fluorescence were seen in the nucleus. We used ddaE for this experiment as a similar class I da neuron, ddaD, lies next to it and can be used for comparison (Figure S4). By 24h after axon injury the amount of nuclear fluorescence in ddaE compared to its uninjured ddaD neighbor had increased about four-fold (Figure S4). We therefore used this as a reporter for JNK signaling after dendrite injury. When we tracked puc-GFP levels in ddaE neurons after dendrite removal, no increase in fluorescence was observed (Figure S4). We conclude that the DLK/JNK pathway is neither required for the response to dendrite injury nor activated by it. Thus dendrite injury triggers regenerative growth without using the conserved axon injury signal transduction cascade.

Discussion

It has not previously been clear whether mature neurons have a surveillance mechanism that allows them to respond to dendrite injury. We demonstrate that dendrite removal triggers robust reinitiation of dendrite outgrowth in multiple neuron types, even after development of dendrite shape is complete. Unlike previous studies that have examined the response to removal of single dendrites, we find that dendrite regeneration is not restricted to a specific developmental window, or to neurons with complex dendrite arbors. Instead our data suggest that dendrite regeneration may be a property of many neurons throughout life. It is also interesting to note that different cell types seem to complete dendrite regrowth in distinct ways. Not surprisingly, neurons that respond to pain regrew dendrites until their normal territory was covered. Intriguingly, neurons responsible for proprioception regrew dendrites until they had regained the normal number of dendrite branch points.

This difference in how regeneration is completed can account for some of the differences between our conclusions and those made in previous studies. Area of coverage was previously assayed as a key aspect of all types of dendrite regeneration (Song et al., 2012; Sugimura et al., 2003), and so the response of ddaE to removal of a single dendrite was not noted even though an increase in complexity of the remaining dendrite is clear in the published data (Song et al., 2012). By performing complete dendrite removal, we were able to get much more striking results to demonstrate the ability of multiple cell types to respond to dendrite injury.

Our data suggest that neurons possess at least two different injury surveillance systems: (1) signaling through DLK informs the cell body of axon injury, and (2) an independent signal is responsible for informing the cell body of dendrite injury. A previous study suggested that the Akt kinase may be a shared component of axon and dendrite regeneration (Song et al., 2012). Perhaps Akt is generally required to promote cell growth downstream of specific regulators that inform the cell of axon or dendrite injury.

If the DLK pathway does not signal dendrite injury, what type of surveillance machinery might monitor dendrites? It seems likely that transcription changes are required to allow growth of a new dendrite arbor. Perhaps a signal is generated at the site of injury and transported back to the cell body in the same way that has been proposed for axons (Abe and Cavalli, 2008; Rishal and Fainzilber, 2010). In this case, however, the retrograde motor should be a kinesin rather than dynein since microtubules have minus-end-out orientation in Drosophila dendrites (Stone et al., 2008). Alternately, a change in electrical signals arising from dendrites could directly regulate transcription factors in the cell body. It will be very interesting to explore different types of injury signals in the future.

The ability of mature neurons to initiate new growth in response to large-scale dendrite damage could play an important role in recovery from stroke, seizure and TBI. Considerable neurite sprouting occurs during recovery from these conditions (Nudo, 2006) and so it is possible that both axon and dendrite outgrowth are triggered. If so, it seems likely that they are triggered through separate signaling pathways as DLK is required for injury-induced axon outgrowth, but not injury-induced dendrite outgrowth. By establishing a tractable genetic model for dendrite regeneration, we should be able to identify key players in this process. Having a molecular handle on this uncharacterized type of regeneration will allow us to probe its importance in mammalian models of nervous system trauma.

Experimental Procedures

Labeling identified neurons in Drosophila larvae and adults

For most experiments UAS-mCD8-GFP was expressed in neuronal subsets to identify specific neurons in whole animals. UAS-EB1-GFP was used to analyze microtubule polarity and dynamics. GFP markers were expressed in class I neurons with 221-Gal4 and class IV neurons with either 477-Gal4 (larvae) or ppk-Gal4 in adults. For more detailed information about genotypes please see the Supplemental Experimental Procedures.

Axon and dendrite injury

In both larvae and adults, individual axons or dendrites were severed at their base with a pulsed UV laser (Micropoint, Andor Technology). In all cases whole living animals were mounted for laser surgery, and were recovered to normal growth conditions immediately after severing. Animals were remounted for imaging at later timepoints. Please see the Supplemental Experimental Procedures for more details about imaging conditions.

Supplementary Material

01

Highlights.

  • After dendrite removal neurons regrow dendrites rather than die.

  • Dendrite regeneration is robust in larval and adult Drosophila neurons.

  • Dendrites regrow to recapitulate either complexity or coverage.

  • Dendrite regeneration does not rely on a conserved axon regeneration pathway.

Acknowledgments

We are very grateful to the Bloomington Drosophila Stock Center, the Vienna Drosophila RNAi Center and FlyTrap; all are invaluable resources. Catherine Collins, Wesley Grueber and Dirk Bohmann generously provided us with Drosophila stocks. Tadashi Uemura provided helpful information for imaging da neurons in adults. Michelle Nguyen kindly helped collect flies and embryos. This work was funded by the NIH (R01 GM085115) and MMR was a Pew Scholar in the Biomedical Sciences.

Footnotes

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