Morphological evidence that regenerating axons can fuse with severed axon segments

DeRiemer, Susan A.; Elliott, Ellen J.; Macagno, Eduardo R.; Muller, Kenneth J.

doi:10.1016/0006-8993(83)90373-6

Cited by 55 publications

(42 citation statements)

References 22 publications

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“…EFF-1, a trimeric fusogen similar to class-II viral fusion proteins 14,15 , mediates a wide range of fusion events in C. elegans 16,17 , including the sculpting of dendritic arbors through self-fusion of excessive branches 18 . Animals lacking EFF-1 displayed a strong defect in axonal fusion 1 ( Figure 2.1c,d).…”

Section: Introduction and Resultsmentioning

confidence: 99%

“…Fusion between individual neurons has also been reported to occur during axonal repair after injury, first in the leech several decades ago 16 and more recently in C. elegans 2,3 . Although the fusion between the regrowing proximal fragment and its own distal fragment is generally specific, it has been reported that when two or more fasciculating axons are simultaneously transected, the regrowing proximal axonal fragment of one neuron can fuse with the proximal or distal axonal fragment of the nearby injured neuron 2,16 .…”

Section: Ectopic Neuronal Cell-cell Fusion During Axonal Regenerationmentioning

confidence: 99%

“…In this case, following transection of the axon, the proximal axonal fragment that is still attached to the cell body regrows toward and fuses with its own separated axonal fragment ( Figure 5.1C), re-establishing membrane and cytoplasmic continuity and therefore the original axonal tract. This process has been recognized for more than 50 years, and has been described in the motor neurons of crayfish 14 , sensory neurons of the leech 15,16 , giant axons of the earthworm 17 , dissociated Aplysia sensory neurons in vitro 18 and, more recently, in the mechanosensory neurons of the nematode C. elegans 2,19 . In these studies, cytoplasmic continuity after rejoining of the two separated fragments was confirmed by electron microcopy 2,15,17,19 , by injection of high molecular weight dyes (such as horseradish peroxidase) into the soma 16 , or by expressing genetically encoded photoconvertible fluorophores such as Kaede 2 , which were able to diffuse through the fusion site, from the soma to the distal axonal fragment.…”

Section: Axonal Fusion To Repair An Injured Axonmentioning

confidence: 99%

“…This process has been recognized for more than 50 years, and has been described in the motor neurons of crayfish 14 , sensory neurons of the leech 15,16 , giant axons of the earthworm 17 , dissociated Aplysia sensory neurons in vitro 18 and, more recently, in the mechanosensory neurons of the nematode C. elegans 2,19 . In these studies, cytoplasmic continuity after rejoining of the two separated fragments was confirmed by electron microcopy 2,15,17,19 , by injection of high molecular weight dyes (such as horseradish peroxidase) into the soma 16 , or by expressing genetically encoded photoconvertible fluorophores such as Kaede 2 , which were able to diffuse through the fusion site, from the soma to the distal axonal fragment. In some models, neuronal function has also been shown to recover fully at the electrophysiological 14,15,17,18 and behavioral levels 14,17 .…”

Section: Axonal Fusion To Repair An Injured Axonmentioning

confidence: 99%

“…RAB-5 and its mammalian ortholog Rab5 localize to early endosomes and play important roles in endocytosis. They facilitate transport of clathrin-coated vesicles to early endosomes, fusion between endosomes, and cargo trafficking from endosomes into lysosomes for degradation [14][15][16][17][18] . Depletion phenotypes of RAB-5 largely involve defects in protein internalization from the membrane.…”

Section: Introductionmentioning

confidence: 99%

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Function and regulation of the fusogen EFF-1 during axonal repair

Linton¹

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In the current clinical environment, treatment options for nerve and spinal cord injuries remain limited. To develop novel therapies, we require a better understanding of axonal repair and its underlying molecular mechanisms. The response of an axon to a transection injury is complex: the axon still attached to the cell body begins a process of regenerative regrowth, whereas a concurrent process of degeneration is activated in the severed axonal fragment. Characterizing ways in which the axon can achieve repair, involving both regeneration and degeneration, is crucial to making progress in a clinical setting.We have studied a means of axonal repair called axonal fusion, which occurs spontaneously in the mechanosensory neurons of the nematode C. elegans. Following axotomy with a UV laser, the regrowing axonal fragment is able to directly fuse with its own severed fragment, re-establishing continuity. When axonal fusion was first described in C. elegans, the molecular pathways involved were unknown, and the only protein associated with the process was the fusogen Epithelial Fusion Failure-1 (EFF-1). EFF-1 is a nematode-specific transmembrane glycoprotein that acts to fuse plasma membranes. It has been studied extensively in other C. elegans tissues, but its function and regulation in neurons have been largely uncharacterized.In this context, we aimed to further understand the role of EFF-1 in axonal repair, focusing on its potential contribution to both regeneration and degeneration, and the mechanisms that regulate its fusogenic activity. We approached these biological questions using a combination of genetic and molecular biology techniques available in the C. elegans model system.The following chapters characterize EFF-1 function and regulation in the C. elegans mechanosensory neuron PLM. Firstly, we demonstrate a cell-autonomous role for EFF-1 in axonal fusion, and show that it has a dynamic localization pattern in the regenerating axon, whereby it is mobilized to the membrane of the regenerating growth cone. We also place it downstream in a pathway of apoptotic clearance molecules that allow recognition of the distal axonal fragment.Secondly, we find that neuronal EFF-1 is regulated by the endocytic GTPase RAB-5, with alterations in RAB-5 activity affecting both EFF-1 localization and its function in axonal fusion.Thirdly, we characterize the genes involved in the degeneration of the distal PLM axon following axotomy, and find a remarkable overlap with the molecules involved in regenerative fusion, possibly including EFF-1. Finally, we discuss an intriguing potential role for EFF-1 in mediating neuronal repair through cell-cell fusion. The research detailed here represents significant progress in understanding how a fusogen mediates axonal repair in vivo. It will potentially contribute to the application of axonal fusion as a novel therapy for patients with nerve injuries.ii Declaration by authorThis thesis is composed of my original work, and contains no material previously published or written by an...

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Section: Introduction and Resultsmentioning

confidence: 99%

Section: Ectopic Neuronal Cell-cell Fusion During Axonal Regenerationmentioning

confidence: 99%

Section: Axonal Fusion To Repair An Injured Axonmentioning

confidence: 99%

Section: Axonal Fusion To Repair An Injured Axonmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Function and regulation of the fusogen EFF-1 during axonal repair

Linton¹

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A detached branch stops being recognized as self by other branches of a neuron

Wang

Macagno

1998

J. Neurobiol.

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The multiple peripheral projections of a single leech mechanosensory neuron form individual arbors that do not overlap at all with each other, a phenomenon that has been termed “self‐avoidance” (Yau, 1976; Kramer and Stent, 1985). This is in marked contrast to the peripheral arbors of adjacent segmental homologues, which partially overlap with each other at their boundaries in target areas of the body wall (Nicholls and Baylor, 1968; Gan and Macagno, 1995). How a neurite differentiates between sibling neurites of the same cell and those of a homologue is not known, but possible mechanisms include the recognition of surface markers of neuronal identity or the detection of cell‐specific patterns of activity. In order to test whether this self‐recognition requires a neurite to be in direct communication with its soma, we used a laser microbeam to sever a branch of a dye‐filled pressure‐sensitive (P) neuron in an intact leech embryo. Time‐lapse observations of the P cell arbor in the living, unanesthetized, animal for up to 24 h following the surgery showed that the detached branch continued to show dynamic growth behavior throughout the period of observation. However, the detached branch ceased being avoided by the rest of the cell within a few hours, other, attached branches of the neuron overgrowing its territory and directly overlapping with it. Our experiments provide direct evidence for the existence of strong growth‐inhibiting interactions between sibling processes, and indicate that self‐avoidance by the growing neurites of a cell requires physical continuity between these neurites. © 1998 John Wiley & Sons, Inc. J Neurobiol 35: 53–64, 1998

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Effect of temperature on long‐term survival of anucleate giant axons in crayfish and goldfish

Blundon

Sheller

Moehlenbruck

et al. 1990

J of Comparative Neurology

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The effect of temperature on the electrophysiology and morphology of anucleate axons was examined following severance of crayfish medial giant axons and goldfish Mauthner axons from their respective cell bodies. Although anucleate segments of each giant axon exhibited long-term survival for weeks to months at 5-25 degrees C in crayfish and 10-30 degrees C in goldfish, the two axons differed in their survival characteristics. All measures of long-term survival in crayfish medial giant axons were independent of animal holding temperature, whereas all measures in Mauthner axons were dependent on holding temperature. Medial giant axons survived for at least 90 days in crayfish maintained at 5-25 degrees C in this and previous studies. Mauthner axons survived for over 5 months in goldfish maintained at 10 degrees C but survived for 1 month at 30 degrees C. Postoperative time had different effects on many single measures of long-term survival (axonal diameter, amplitude of action or resting potentials) in medial giant axons compared to Mauthner axons. For example, resting and action potentials in crayfish medial giant axons remained remarkably constant at all holding temperatures for 0-90 postoperative days. In contrast, resting and action potentials in goldfish Mauthner axons declined abruptly in the first 10-20 postoperative days followed by a slower decline at each holding temperature. We suggest that the mechanism of long-term survival is not necessarily the same in all anucleate axons.

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Morphological evidence that regenerating axons can fuse with severed axon segments

Cited by 55 publications

References 22 publications

Function and regulation of the fusogen EFF-1 during axonal repair

Function and regulation of the fusogen EFF-1 during axonal repair

A detached branch stops being recognized as self by other branches of a neuron

Effect of temperature on long‐term survival of anucleate giant axons in crayfish and goldfish

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