Cerebellar heterokaryon formation increases with age and after irradiation

Wiersema, A. K.; Dijk, F; Dontje, Bert; Want, J.J.L. van der; Haan, Gerald de

doi:10.1016/j.scr.2008.02.001

Cited by 17 publications

(16 citation statements)

References 11 publications

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“…An increase in fusion rate with aging has also been found in irradiated models 53,60 , supporting the idea that aging somehow favors the acquisition of fusion competence by neurons. The contribution of hematopoietic cells to Purkinje neurons can occur in physiological conditions; however, these cells were found to be mononucleated, suggesting that fusion might be a transient event or that another mechanism is in place 63 .…”

Section: Cell-cell Fusion Between Neurons and Stem Cellssupporting

confidence: 58%

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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: Cell-cell Fusion Between Neurons and Stem Cellssupporting

confidence: 58%

“…In the past decade, it has become clear that cell-cell fusion is a key mechanism through which stem or 60,65 . An increase in fusion rate with aging has also been found in irradiated models 53,60 , supporting the idea that aging somehow favors the acquisition of fusion competence by neurons.…”

Section: Cell-cell Fusion Between Neurons and Stem Cellsmentioning

confidence: 99%

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

Linton¹

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“…The discovery that BM-derived Purkinje cells resulted from fusion events, led to several studies over the next few years attempting to further understand this phenomenon. In both humans and rodents, without additional pathology such as inflammation, Purkinje cell fusion appeared to occur at very low levels, though the frequency of fusion events was thought to increase with age [ 23 , 45 , 46 ]. It was, however, debated whether many of these studies were conducted under physiological conditions as the patients or animals were subjected to highly invasive regimens involving either irradiation or chemotherapeutic drugs to remove the host haematopoietic system.…”

Section: Introductionmentioning

confidence: 99%

Cell fusion in the brain: two cells forward, one cell back

2014

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Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell fusion, shown by detection of increased bi-nucleated neurons, has also been described in a variety of human central nervous system diseases, including both multiple sclerosis and Alzheimer’s disease. Accumulating evidence is therefore raising new questions into the biological significance of cell fusion, with the possibility that it represents an important means of cell-mediated neuroprotection or rescue of highly complex neurons that cannot be replaced in adult life. Here, we discuss the evidence behind this phenomenon in the rodent and human brain, with a focus on the subsequent research investigating the physiological mechanisms of cell fusion underlying this process. We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

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“…Cell fusion events in uninjured tissues are typically rare (2) and difficult to detect (12). In contrast, fusion events may increase markedly in the presence of tissue injury (5,6,13,14). For some cell types, such as lung alveolar type II cells, the majority of bone marrow derivatives that contribute to the pool of type II cells may arise from cell fusion events.…”

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confidence: 99%

“…Whether cell fusion has a beneficial or detrimental impact on steady-state tissue dynamics or disease pathology is still not clear. In some cases, cell fusion has been shown to preserve cerebellar Purkinje neurons that have a limited adult population size (4,5,6,13) or even to reverse a heritable disease phenotype in a mouse model of tyrosinemia type I (10,15). In other cases, cell fusion has been shown to play a role in disease pathology (9).…”

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confidence: 99%

Incomplete reprogramming after fusion of human multipotent stromal cells and bronchial epithelial cells

et al. 2010

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Bone marrow-derived progenitor cells can fuse with cells of several different tissues, including lung, especially following injury. Despite many reports of cell fusion, few studies have examined the function of the resulting hybrid cells. We cocultured human multipotent stromal cells (hMSCs) and normal human bronchial epithelial cells (NHBEs) and observed the formation of hMSC/NHBE heterokaryons. The heterokaryons expressed several proteins characteristic of epithelial cells, such as keratin and occludin. Hybrid cells also expressed the mRNAs and proteins for 2 important ion channels that maintain bronchial and alveolar fluid balance: the cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial Na(+) channel (ENaC). By immunocytochemistry, CFTR was expressed in many hybrid cells but was absent or low in others. Whole-cell patch-clamp recordings demonstrated a glibenclamide-sensitive current in the presence of barium chloride, consistent with functional CFTR channels, in control NHBEs and hMSC/NHBE heterokaryons. Total cell capacitance measurements showed that the membrane surface area of heterokaryons was similar to that of NHBEs. Heterokaryons expressed the α- and γ-ENaC subunits but did not express the β-ENaC subunit, indicating the inability to form a complete ENaC channel. In addition, hybrid cells formed by the fusion of hMSCs with immortalized bronchial cells that expressed CFTR ΔF508 did not lead to reprogramming of the hMSC nucleus and expression of wild-type CFTR mRNA. Our data show that reprogramming can be incomplete following fusion of adult progenitor cells and somatic cells and may lead to altered cell function.

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Cerebellar heterokaryon formation increases with age and after irradiation

Cited by 17 publications

References 11 publications

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

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

Cell fusion in the brain: two cells forward, one cell back

Incomplete reprogramming after fusion of human multipotent stromal cells and bronchial epithelial cells

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