An invasive podosome-like structure promotes fusion pore formation during myoblast fusion

Sens, K.; Zhang, Shiliang; Jin, Peng; Duan, Rui; Zhang, Guofeng; Luo, Fengbao; Parachini, Lauren; Chen, Elizabeth H.

doi:10.1083/jcb.201006006

Cited by 183 publications

(432 citation statements)

References 67 publications

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“…A variety of fusion-related roles for Drosophila WASp have been proposed, including involvement in establishment of an adhesive structure between myoblasts (30), expansion of nascent fusion pores (21,26), and contribution to the formation of fusion-associated F-actin "foci" (27,32). At present, our analysis does not allow for assignment of such specific cellular roles to N-WASp as a mediator of mammalian myoblast fusion.…”

Section: Discussioncontrasting

confidence: 41%

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The actin regulator N-WASp is required for muscle-cell fusion in mice

Gruenbaum-Cohen

Harel²,

Umansky³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A fundamental aspect of skeletal myogenesis involves extensive rounds of cell fusion, in which individual myoblasts are incorporated into growing muscle fibers. Here we demonstrate that N-WASp, a ubiquitous nucleation-promoting factor of branched microfilament arrays, is an essential contributor to skeletal muscle-cell fusion in developing mouse embryos. Analysis both in vivo and in primary satellite-cell cultures, shows that disruption of N-WASp function does not interfere with the program of skeletal myogenic differentiation, and does not affect myoblast motility, morphogenesis and attachment capacity. N-WASp-deficient myoblasts, however, fail to fuse. Furthermore, our analysis suggests that myoblast fusion requires N-WASp activity in both partners of a fusing myoblast pair. These findings reveal a specific role for N-WASp during mammalian myogenesis. WASp-family elements appear therefore to act as universal mediators of the myogenic cell-cell fusion mechanism underlying formation of functional muscle fibers, in both vertebrate and invertebrate species.actin nucleation | myotube formation

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Section: Discussioncontrasting

confidence: 41%

“…Noteworthy in this context is the observed requirement for Nap1, a regulator of the WAVE NPF, during fusion of cultured murine myogenic cell lines (25). An essential involvement of WASp/WAVE-family elements in myoblast fusion has been previously established for the different phases of Drosophila myogenesis (21,(26)(27)(28)(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

The actin regulator N-WASp is required for muscle-cell fusion in mice

Gruenbaum-Cohen

Harel²,

Umansky³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies have shown that, in founder cells, F-actin forms a thin sheath underlying points of cell contact (Sens et al, 2010). By contrast, within the limits of confocal microscopy, the dense actin focus appears to reside exclusively in the FCMs (Sens et al, 2010;Haralalka et al, 2011), as depicted in Figs 4, 5 and 7. These F-actin foci are formed by the action of the NPFs Scar and WASp on the Arp2/3 complex as outlined below.…”

Section: F-actin Foci F-actin Nucleating Complexes and Fusion Poresmentioning

confidence: 98%

“…Dynamic F-actin foci are formed and dissolve coincident with myoblast fusion in live embryos (Richardson et al, 2007), and actin foci are found at points of cell-cell contact in fixed tissue samples (Kesper et al, 2007;Richardson et al, 2007;Kim et al, 2007). Recent studies have shown that, in founder cells, F-actin forms a thin sheath underlying points of cell contact (Sens et al, 2010). By contrast, within the limits of confocal microscopy, the dense actin focus appears to reside exclusively in the FCMs (Sens et al, 2010;Haralalka et al, 2011), as depicted in Figs 4, 5 and 7.…”

Section: F-actin Foci F-actin Nucleating Complexes and Fusion Poresmentioning

confidence: 99%

Myoblast fusion: lessons from flies and mice

2012

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The fusion of myoblasts into multinucleate syncytia plays a fundamental role in muscle function, as it supports the formation of extended sarcomeric arrays, or myofibrils, within a large volume of cytoplasm. Principles learned from the study of myoblast fusion not only enhance our understanding of myogenesis, but also contribute to our perspectives on membrane fusion and cell-cell fusion in a wide array of model organisms and experimental systems. Recent studies have advanced our views of the cell biological processes and crucial proteins that drive myoblast fusion. Here, we provide an overview of myoblast fusion in three model systems that have contributed much to our understanding of these events: the Drosophila embryo; developing and regenerating mouse muscle; and cultured rodent muscle cells. IntroductionThe process of fusing two adjacent membranes accomplishes many goals that are crucial to the development and maintenance of living organisms. Broadly, membrane fusion can occur intracellularly, as with synaptic vesicles, or between cells, as for sperm-egg fusion. Cell fusion occurs in a broad range of organisms, including Saccharomyces cerevisiae and Caenorhabditis elegans, and between several cell types, such as macrophages, placental trophoblasts and myoblasts. Experimental analysis of fusion in these systems has revealed the involvement of a diverse array of specialized molecules.Myoblast fusion, a fundamental step in the differentiation of muscle in most organisms, can involve tens of thousands of myoblasts, Given the complexity of the musculature, fusion must be a regulated process in which the appropriate number of cells fuse at the appropriate time and place. Often these cells migrate long distances prior to fusion, and fusion can involve multiple cell types, necessitating cell recognition and adhesion, which are crucial to accurate and efficient fusion. In addition to the early fusion events that occur during embryogenesis, vertebrate muscle tissue is able to regenerate in response to damage and disease. This regeneration involves proliferation of muscle satellite cells (see Glossary, Box 1) and their subsequent fusion to repair the damaged muscles. The focus of this review is the process of myoblast fusion, which involves cell migration, adhesion and signaling transduction pathways leading up to the actual fusion event. We review the crucial role of the actin cytoskeleton and actin polymerizing proteins, and recently revealed membrane protrusions that may drive fusion itself. We describe three powerful systems for this analysis: Drosophila embryogenesis; mouse embryogenesis and regeneration; and rodent tissue culture. We highlight the genes and morphological events involved in myoblast fusion, as revealed by each system. With the emergence of Danio rerio as another model for myoblast fusion, we also list relevant homologs in this system (Tables 1, 2). Experimental systems for the analysis of myoblast fusionThe ability to isolate and propagate mammalian myoblasts that could differentiate and fuse in...

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“…The signaling intermediates include scaffold proteins (ELMO, Blown Fuse, Antisocial) (8)(9)(10), kinase (p21-activated kinase) (11), guanine nucleotide exchange factors (GEFs) [Myoblast City (MBC), Loner] (12, 13), GTPase (Rac), (14) and actin nucleation regulators (Kette, WAVE, WASP, WASP-interacting protein) (15)(16)(17)(18)(19). Some of these proteins ultimately promote the formation of actin-driven podosome-like structures in the fusion-competent cells that invade founder cells for membrane fusion (20,21).…”

mentioning

confidence: 99%

G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates

Hamoud

Tran

Croteau

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

113

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Muscle fibers form as a result of myoblast fusion, yet the cell surface receptors regulating this process are unknown in vertebrates. In Drosophila, myoblast fusion involves the activation of the Rac pathway by the guanine nucleotide exchange factor Myoblast City and its scaffolding protein ELMO, downstream of cellsurface cell-adhesion receptors. We previously showed that the mammalian ortholog of Myoblast City, DOCK1, functions in an evolutionarily conserved manner to promote myoblast fusion in mice. In search for regulators of myoblast fusion, we identified the G-protein coupled receptor brain-specific angiogenesis inhibitor (BAI3) as a cell surface protein that interacts with ELMO. In cultured cells, BAI3 or ELMO1/2 loss of function severely impaired myoblast fusion without affecting differentiation and cannot be rescued by reexpression of BAI3 mutants deficient in ELMO binding. The related BAI protein family member, BAI1, is functionally distinct from BAI3, because it cannot rescue the myoblast fusion defects caused by the loss of BAI3 function. Finally, embryonic muscle precursor expression of a BAI3 mutant unable to bind ELMO was sufficient to block myoblast fusion in vivo. Collectively, our findings provide a role for BAI3 in the relay of extracellular fusion signals to their intracellular effectors, identifying it as an essential transmembrane protein for embryonic vertebrate myoblast fusion. myotube formation | myogenesis | model system | ced-12 | RhoGTP

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An invasive podosome-like structure promotes fusion pore formation during myoblast fusion

Abstract: An F-actin–enriched protrusion resembling an invasive podosome promotes fusion pore formation between muscle founder cells and fusion-competent myoblasts.

Cited by 183 publications

References 67 publications

The actin regulator N-WASp is required for muscle-cell fusion in mice

The actin regulator N-WASp is required for muscle-cell fusion in mice

Myoblast fusion: lessons from flies and mice

G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates

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