Ultrastructural analysis of interneuronal syncytial perforations

Os, Sotnikov; Paramonova, N. M.; Арчакова, Л. И.

doi:10.1042/cbi20090160

Cited by 4 publications

(6 citation statements)

References 8 publications

(7 reference statements)

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“…We observed a similar phenotype in animals deficient in UNC-70/β-spectrin, a genetic background in which the axons of C. elegans motor neurons undergo spontaneous cycles of breaks followed by regeneration 30 . We observed that unc-70 mutant animals display aberrant PLM axonal morphology …”

Section: Introduction and Resultssupporting

confidence: 54%

“…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.…”

Section: Post-translational Regulation Of Eff-1mentioning

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 .…”

mentioning

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. …”

mentioning

confidence: 99%

“…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 .…”

mentioning

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 Resultssupporting

confidence: 54%