The question of the fusion of neuron processes

Os, Sotnikov; Rybakova, G. I.; Соловьева, И. А.

doi:10.1007/s11055-008-9064-8

Cited by 2 publications

(6 citation statements)

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“…Work in cell culture has revealed that only the transmembrane isoforms A and B were capable of mediating cellcell fusion 29 , and only isoform A has been found to rescue morphological defects in vivo 34 .…”

Section: Discussionmentioning

confidence: 99%

“…It has a crucial role in fusing a variety of C. elegans cells during normal development to generate syncytia 25 . This molecule is also able to mediate membrane fusion in vitro in other cellular contexts [26][27][28][29][30][31] . EFF-1 must be inserted into both membranes to mediate fusion; current models suggest that its mechanism of action involves the formation of trimers in trans across apposing membranes 28,31 .…”

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“…While this would appear to be a clue as to how EFF-1 mediates fusion, current evidence suggests that EFF-1 acts through its own distinct fusion mechanism (Figure 1.3). Unlike viral fusogens, EFF-1 is required on both cell membranes to mediate fusion, both in vitro and in vivo 26,27,29,30 . The current working model is that, prior to fusion, EFF-1 exists as a monomer in an upright position on the membrane 31 .…”

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confidence: 99%

“…EFF-1 localization has been characterized in multiple tissue and cell types, albeit with somewhat varied results. In some cells, EFF-1 has been observed accumulating at cell-cell borders prior to fusion 29,30,34,82 . However, another study using immunostaining demonstrated that endogenous EFF-1 instead localized predominantly to intracellular compartments, and was present only transiently at the membrane.…”

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confidence: 99%

“…Recruitment of EFF-1 to fusion sites in larval hypodermal cells was shown to be mediated at least in part by the actin regulator ), but other pathways may also exist. Much has been characterized about the molecular cascades that are activated in regenerating axons [28][29][30] and it is plausible that some of these molecules play a currently uncharacterized role in EFF-1 recruitment. …”

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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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Linton¹

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Cell-cell fusion in the nervous system: Alternative mechanisms of development, injury, and repair

Giordano-Santini

Linton

Hilliard

2016

Seminars in Cell & Developmental Biology

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Over a century ago, the seminal work of Ramón y Cajal revealed that the nervous system is made of individual units, the neurons, which are related to each other by contiguity rather than continuity. This view overturned the idea that the nervous system was a reticulum of fibers, a rete diffusa nervosa, as proposed and defined by Camillo Golgi. Although the neuron theory has been widely confirmed in every model system studied and constitutes the basis of modern neuroscience, evidence accumulated over the years suggests that neurons, similar to other types of cells, have the potential to fuse their membranes and undergo cell-cell fusion under certain conditions. This concept adds a substantial layer to our view of the nervous system and how it functions. Here, we bring together past and more recent discoveries on multiple aspects of neuronal fusion, discussing how this cellular event is generated, and what consequences it has for our understanding of nervous system development, disease, injury, and repair.

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The question of the fusion of neuron processes

Cited by 2 publications

References 8 publications

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

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

Cell-cell fusion in the nervous system: Alternative mechanisms of development, injury, and repair

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