Axon regeneration in C. elegans: Worming our way to mechanisms of axon regeneration

Byrne, Alexandra B.; Hammarlund, Marc

doi:10.1016/j.expneurol.2016.08.015

“…The ability of vertebrate zebrafish to fully recover following complete spinal cord transection has provided unique insights into the role of non-neuronal cells in the regenerative response 17 . The nematode Caenorhabditis elegans provides several unique advantages, including optical transparency, the possibility of genetic manipulation and the availability of methods to axotomize single axons with a laser 14 . A number of different injury paradigms have also been used in the larval and adult nervous system of the fruitfly Drosophila melanogaster , which also enables the power of live imaging to be combined with genetic manipulation 16 .…”

Section: Figmentioning

confidence: 99%

“…Other aspects of axon regeneration, which include the roles of the cellular environment, axon–soma signalling and growth cone formation and dynamics have been extensively covered in recent reviews 4,5,8,10–13 and will not be discussed here. This Review largely focuses on studies on mice, as recent reviews have covered axon regeneration in other model systems including C. elegans 14,15 , Drosophila melanogaster 16 and fish 17 .…”

mentioning

confidence: 99%

Intrinsic mechanisms of neuronal axon regeneration

Mahar

¹

,

Cavalli

²

2018

View full text Add to dashboard Cite

Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.

show abstract

“…Recruitment of EFF-1 to fusion sites in larval hypodermal cells has been shown to be mediated at least in part by the actin regulator VAB-10 (Yang et al, 2017), although other pathways may also exist. The molecular cascades that are activated in regenerating axons have been well characterized (El Bejjani and Hammarlund, 2012;Hammarlund and Jin, 2014;Byrne and Hammarlund, 2017) and it is plausible that some of these molecules play a currently uncharacterized role in EFF-1 recruitment. However, overactivity of RAB-5 did lead to accumulation of EFF-1 in enlarged RAB-5-positive compartments (Fig.…”

Section: Discussionmentioning

confidence: 99%

Disruption of RAB-5 Increases EFF-1 Fusogen Availability at the Cell Surface and Promotes the Regenerative Axonal Fusion Capacity of the Neuron

Linton

¹

,

Riyadh

²

,

Ho

³

et al. 2019

View full text Add to dashboard Cite

Following a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments. In the nematode Caenorhabditis elegans, this highly efficient regenerative axonal fusion is mediated by epithelial fusion failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is an important step toward a better understanding of this repair process. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Therefore, we find that perturbing RAB-5 activity is sufficient to restore axonal fusion in mutant animals with decreased axonal fusion capacity. This is accompanied by enhanced membranous localization of EFF-1 and the production of extracellular EFF-1containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion in C. elegans hermaphrodites and the first regulator of EFF-1 in neurons.Peripheral and central nerve injuries cause life-long disabilities due to the fact that repair rarely leads to reinnervation of the target tissue. In the nematode Caenorhabditis elegans, axonal regeneration can proceed through axonal fusion, whereby a regrowing axon reconnects and fuses with its own separated distal fragment, restoring the original axonal tract. We have characterized axonal fusion and established that the fusogen epithelial fusion failure-1 (EFF-1) is a key element for fusing the two separated axonalfragmentsbacktogether.Here,weshowthatthesmallGTPaseRAB-5isakeycell-intrinsicregulatorof the fusogen EFF-1 and can in turn regulate axonal fusion. Our findings expand the possibility for this process to be controlled and exploited to facilitate axonal repair in medical applications.

show abstract

“…Much has been characterized about the molecular cascades that are activated in regenerating axons [34][35][36] and it is plausible that some of these molecules play a currently uncharacterized role in EFF-1 recruitment.…”

Section: Discussionmentioning

confidence: 99%

RAB-5 regulates regenerative axonal fusion by controlling EFF-1 endocytosis

Linton

¹

,

Neumann

²

,

Giordano-Santini

³

et al. 2018

Preprint

View full text Add to dashboard Cite

Following a transection injury to the axon, neurons from a number of species have the ability to undergo spontaneous repair via fusion of the two separated axonal fragments.In the nematode C. elegans, this highly efficient regenerative axonal fusion is mediated by Epithelial Fusion Failure-1 (EFF-1), a fusogenic protein that functions at the membrane to merge the two axonal fragments. Identifying modulators of axonal fusion and EFF-1 is the next step towards harnessing this process for clinical applications. Here, we present evidence that the small GTPase RAB-5 acts to inhibit axonal fusion, a function achieved via endocytosis of EFF-1 within the injured neuron. Consequently, we find that perturbing RAB-5 activity increases the capacity of the neuron to undergo axonal fusion, through enhanced membranous localization of EFF-1 and the production of extracellular EFF-1-containing vesicles. These findings identify RAB-5 as a novel regulator of axonal fusion and the first regulator of EFF-1 in neurons.

show abstract

Axon regeneration in C. elegans: Worming our way to mechanisms of axon regeneration

Cited by 35 publications

References 98 publications

Intrinsic mechanisms of neuronal axon regeneration

Intrinsic mechanisms of neuronal axon regeneration

Disruption of RAB-5 Increases EFF-1 Fusogen Availability at the Cell Surface and Promotes the Regenerative Axonal Fusion Capacity of the Neuron

RAB-5 regulates regenerative axonal fusion by controlling EFF-1 endocytosis

Contact Info

Product

Resources

About