The hallmarks of cell-cell fusion

Hernandez, Javier M.; Podbilewicz, Benjamin

doi:10.1242/dev.155523

Cited by 172 publications

(196 citation statements)

References 200 publications

(269 reference statements)

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“…Cell-cell fusion is a highly coordinated, tightly regulated, multi-step process, which requires synergistic actions of multiple fusion machineries [1][2][3]9 . The known mammalian fusogens show clear celltype specific distribution 1-3 .…”

Section: Discussionmentioning

confidence: 99%

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

Zhang

Grabau

et al. 2019

Preprint

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AbstractCell-cell fusion or syncytialization is fundamental to the reproduction, development and homeostasis of multicellular organisms. In addition to various cell-type specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell-fusion events. Nevertheless, molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an indispensable role in placental trophoblast fusion by translocating PS to the cell surface independent of apoptosis. Consistent with its essential role in trophoblast fusion, the placentas from TMEM16F-deficient mice exhibit deficiency in syncytialization, placental developmental defects and perinatal lethality. Our findings thus identify a cell-cell fusion mechanism by which TMEM16F CaPLSase-dependent externalization of PS serves as a critical cell fusion signal to facilitate trophoblast syncytialization and placental development.

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Section: Discussionmentioning

confidence: 99%

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

Zhang

Grabau

et al. 2019

Preprint

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“…The musclespecific membrane micropeptides, myomaker and myomixer (a.k.a. minion or myomerger), have been reported to regulate myoblast fusion (Bi et al, 2017;Millay et al, 2013;Zhang et al, 2017), with myomaker sufficient to induce fusion of non-muscle cells into myoblasts, which is enhanced by myomixer co-expression (Hernandez and Podbilewicz, 2017). Although numerous proteins and actinmyosin components have been implicated in myoblast recognition and fusion, the mechanisms driving morphogenesis of plasma membrane and lipid required for the fusion events remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

PIP3 depletion rescues myoblast fusion defects in human rhabdomyosarcoma cells

Lian

Chen

Chou

et al. 2020

Preprint

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StatementThis study reveals a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma cells involving PIP3, whose depletion with PTEN rescues myoblast fusion defects.3 Abstract Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. While the transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs, and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.

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“…From the stalk intermediate, the system may progress to forming a hemifusion diaphragm (13) before the final opening of the fusion pore (8). For the transition from one intermediate to the next, energy barriers such as electrostatic repulsion or steric hydration forces need to be overcome (14)(15)(16). Under physiological conditions, the lifetime of these intermediate states is very short.…”

Section: Introductionmentioning

confidence: 99%

Differential diffusional properties in loose and tight docking prior to membrane fusion

Witkowska

Spindler

Mahmoodabadi

et al. 2020

Preprint

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Fusion of biological membranes, although mediated by divergent proteins, is believed to follow a common pathway. It proceeds through distinct steps including docking, merger of proximal leaflets (stalk formation), and formation of a fusion pore. However, the structure of these intermediates is difficult to study due to their short lifetime. Previously, we observed a loosely and tightly docked state preceding leaflet merger using arresting point mutations in SNARE proteins, but the nature of these states remained elusive. Here we used interferometric scattering (iSCAT) microscopy to monitor diffusion of single vesicles across the surface of giant unilamellar vesicles (GUVs). We observed that the diffusion coefficients of arrested vesicles decreased during progression through the intermediate states. Modeling allowed for predicting the number of tethering SNARE complexes upon loose docking and the size of the interacting membrane patches upon tight docking. These results shed new light on the nature of membrane-membrane interactions immediately before fusion. membrane fusion intermediates | iSCAT microscopy | SNARE proteins | particle tracking | tethered diffusion | GUV Correspondence: rjahn@gwdg.de (R.J.), vahid.sandoghdar@mpl.mpg.de (V.S.), and agata.witkowska@wp.eu (A.W.)

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The hallmarks of cell-cell fusion

Cited by 172 publications

References 200 publications

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

PIP3 depletion rescues myoblast fusion defects in human rhabdomyosarcoma cells

Differential diffusional properties in loose and tight docking prior to membrane fusion

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