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Axon and Dendrite Regeneration in Drosophila Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE No simpler than mammals: axon and dendrite regeneration in Drosophila Homaira Nawabi, Katherine Zukor, and Zhigang He1 F.M. Kirby Neurobiology Center, Children’s Hospital Boston, Boston, Massachusetts 02115, USA Despite important progress made in understanding the for injury models in invertebrates and lower vertebrates mechanisms of axon regeneration, how a neuron re- to complement those in mammals. sponds to an injury and makes a regenerative decision remains unclear. In this issue of Genes & Development, Model systems for regeneration studies Song and colleagues (pp. 1612–1625) investigate axonal and dendritic regeneration in the Drosophila peripheral Albeit infrequently, lower vertebrates and invertebrates nervous system (PNS). With some mechanisms shared have been used for some time in neuronal injury studies, with mammals, this study reveals surprisingly compli- and these studies demonstrate the potential lower organ- cated regenerative responses in terms of cell type, de- isms have for revealing insights into nerve regeneration velopmental stage, and mechanism specificity. With (Spira et al. 2003; Martin et al. 2010; Chen et al. 2011). forward genetic potential, such invertebrates should be Because of their large size and reliable growth ability, powerful in dissecting the cellular and molecular control neurons from Aplysia californica and squid have been of neuronal repair. a powerful model in studying how neurites respond to injury in vivo (Krause et al. 1994; Spira et al. 2003; Erez et al. 2007). With the development of precise femtosecond laser-assisted lesion methods (Yanik et al. 2004), it is also now possible to monitor the live injury responses of In textbooks, regeneration failure has been generally single axons in lower organisms that have much smaller described as an issue of the mammalian CNS. As a result, neurons. Using this method in transgenically labeled the majority of studies have been performed in mammals fluorescent axons in Caenorhabditis elegans, it has been or mammalian neuronal cultures. Through these, it has shown that axons from a variety of neurons, such as the been established that both neuron-intrinsic growth abil- GABAergic motor neurons and mechanosensory neurons, ity and the extracellular environment control the process are able to regenerate after injury. Combining this with of nerve regeneration (Yiu and He 2006; Fitch and Silver powerful genetic screens to find mutations that disrupt 2008; Schwab 2010; Liu et al. 2011; Bradke et al. 2012). this regeneration, several important signaling pathways Importantly, the molecular identities of such extrinsic and molecules controlling the process of axon regenera- and intrinsic contributors are starting to be revealed. tion have been identified (Hammarlund et al. 2009; Yan However, because of technical limitations, mammalian et al. 2009; Bejjani and Hammarlund 2012). Furthermore, models are not easily amenable to some of the powerful now that laser-assisted axotomy can be facilitated with manipulations, such as forward genetic studies and in customized microfluidic devices, C. elegans is poised vivo imaging, that are feasible in lower organisms. It has for high-throughput genetic and pharmacological stud- been assumed that, like the mammalian peripheral ner- ies (Guo et al. 2008; Ghannad-Rezaie et al. 2012). Such vous system (PNS), lower organisms can always regener- axotomy procedures have alsobeenusedinothermodel ate their axons spontaneously. These assumptions, how- organisms, such as zebrafish and Drosophila (Sugimura ever, have not been formally tested in many cases, and et al. 2003; O’Brien et al. 2009; Martin et al. 2010). In a new example to the contrary is presented in the study general, these studies are consistent with the dogma that by Song et al. (2012) in this issue of Genes & Develop- axons in these lower organisms are all capable of re- ment. In addition to revealing important cellular and generation. Recent results, however, demonstrate that molecular insights into the complexity of axon and even this is not always the case. dendrite regeneration, this study highlights the potential Cell type-specific axon regeneration in Drosophila [Keywords: CNS; Pten; bantam; dendritic arborization neuron; microRNA; regeneration] Using such laser-assisted lesioning, Song et al. (2012) 1Corresponding author examined the regenerative responses to axotomy as well E-mail [email protected] Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad. as dendriotomy in Drosophila’s sensory dendritic arbor- 198150.112. ization (da) neurons. Similar to sensory neurons in the GENES & DEVELOPMENT 26:1509–1514 Ó 2012 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/12; www.genesdev.org 1509 Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Nawabi et al. mammalian dorsal root ganglia (DRG), these da neurons’ in the CNS. Instead, these results suggest that these class somas and dendritic branches are located in the periphery, IV neurons are similar to mammalian DRG sensory and their axons travel through peripheral tissues and into neurons, whose axons regenerate well in the periphery the ventral nerve cord (VNC), a part of the Drosophila CNS, but poorly in the CNS. Despite numerous efforts, the to form synapses. Based on dendritic branching morphol- mechanisms that account for the differential responses of ogy, these da neurons can be divided into four classes: class I DRG peripheral and central branches remain unclear. to class IV (Grueber et al. 2002). Class I neurons possess the Future genetic studies on these class IV neurons might simplest dendrite pattern, classes II and III have more provide new insights into this question. complex dendritic fields, and class IV neurons have the most vigorous dendritic arborization (Grueber et al. 2002). Dendrite regeneration Song et al. (2012) found that class IV da neurons are able to regenerate their axons if the lesion occurs in the In contrast to axotomy, very little is known about neuronal peripheral portion of the axon. In contrast, the other responses to dendrite injury. In mammals, it is known that classes fail to elicit a significant regenerative response dendritic remodeling occurs both during development and after axotomy. This is the case even though class III in the adult (Yuste 2011) and that this remodeling can be neurons have a similar dendritic phenotype and are born regulated by neuronal activity (Trachtenberg et al. 2002; at the same time as class IV ones, suggesting that re- Hofer et al. 2009). However, whether injured dendrites are generative capacity is likely independent of dendritic able to regenerate has not been systematically addressed. morphology complexity or developmental timing. Such A major hurdle for such studies is the diffusivity of cell type differences came as a surprise because it has dendritic projection patterns. The laser-assisted focal been assumed that all sensory neurons in the periphery lesioning method, together with transparency of the are regeneration-competent. On the other hand, it is cuticle in Drosophila larvae (Chang and Keshishian known that different types of neurons in the mammalian 1996; Sugimura et al. 2003; Stone et al. 2010), makes it CNS possess distinct regenerative capacities. For exam- feasible to sever single dendrites and monitor their ple, when a permissive graft is transplanted into the regenerative responses in vivo. injured rat spinal cord, propriospinal axons can regrow By doing this in type IV da neurons, Song et al. (2012) into the graft, whereas corticospinal tract axons cannot found that the transected dendrite responds in a binary (Richardson et al. 1982). The results from Song et al. manner: In some cases, the injured dendrites regenerate (2012) suggest that differential regenerative ability can be new branches from the severed stem to reoccupy de- associated with peripheral as well as CNS neurons. nervated space. In other cases, the injured dendrite stalls What could account for such cell type-dependent or retracts, and a neighboring dendrite expands its arbor- differences in regenerative ability? In principle, neuronal ization to occupy the empty field left by the injured one. states, including their regenerative ability, might be spec- Although it is unknown what accounts for such an ‘‘all or ified by gene expression programs. Consistent with this, none’’ response, the refilling of empty space by either recent studies have implicated certain transcription fac- regeneration or sprouting indicates that these neurons tors (such as STAT3 [Smith et al. 2009; Sun et al. 2011], have substantial growth potential. KLFs [Moore et al. 2009; Blackmore et al. 2012], and Strikingly, dendrite regeneration also occurs in a cell CREBs [Gao et al. 2004]) and translational regulators type-specific manner. In contrast to the class IV neurons, (such as mTOR [Park et al. 2008; Liu et al. 2010]) as da neurons in other classes always fail to regenerate their important regulators of intrinsic regenerative ability in injured dendrites. Moreover, the territory denervated by mammalian neurons. In Drosophila da neurons, it is dendriotomy is not refilled by neighboring branches as it is known that certain transcription factors regulate the in class IV neurons. This consistency in cell type specificity diversity and complexity of dendrites (Grueber et al. for both
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