The N-BAR domain protein, Bin3, regulates Rac1- and Cdc42-dependent processes in myogenesis

Simionescu-Bankston, Adriana; Leoni, Giovanna; Wang, Yanru; Pham, Peter P.; Ramalingam, Arivudainambi; DuHadaway, James B.; Faúndez, Víctor; Nusrat, Asma; Prendergast, George C.; Pavlath, Grace K.

doi:10.1016/j.ydbio.2013.07.004

Cited by 28 publications

(30 citation statements)

References 56 publications

(102 reference statements)

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“…Other classes of BAR domain containing proteins may also be important for promoting GRAF-independent muscle fusion. For example, two members of the Bridging integrator (Bin) family, Bin1 and Bin3 have been shown to regulate differentiation and fusion of skeletal myoblasts (Fernando et al, 2009; Simionescu-Bankston et al, 2013; Wechsler-Reya et al, 1998). Interestingly, while Bin3 is an N-BAR only containing protein, recent studies indicate that it, like GRAF1, also regulates actin dynamics.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, while Bin3 is an N-BAR only containing protein, recent studies indicate that it, like GRAF1, also regulates actin dynamics. Simionescu-Bankston et al recently showed that Bin3 associates with and promotes the activation of the Rho-related GTPases Cdc42 and Rac1 in myoblasts (Simionescu-Bankston et al, 2013). Notably, activation of these GTPases is often associated with an inhibition of RhoA; however the effect of Bin3 on RhoA activity was not directly tested in this model.…”

Section: Discussionmentioning

confidence: 99%

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GRAF1 promotes ferlin-dependent myoblast fusion

Lenhart

Becherer

et al. 2014

Developmental Biology

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Myoblast fusion (a critical process by which muscles grow) occurs in a multi-step fashion that requires actin and membrane remodeling; but important questions remain regarding the spatial/temporal regulation of and interrelationship between these processes. We recently reported that the Rho-GAP, GRAF1, was particularly abundant in muscles undergoing fusion to form multinucleated fibers and that enforced expression of GRAF1 in cultured myoblasts induced robust fusion by a process that required GAP-dependent actin remodeling and BAR domain-dependent membrane sculpting. Herein we developed a novel line of GRAF1-deficient mice to explore a role for this protein in the formation/maturation of myotubes in vivo. Post-natal muscles from GRAF1-depleted mice exhibited a significant and persistent reduction in cross-sectional area, impaired regenerative capacity and a significant decrease in force production indicative of lack of efficient myoblast fusion. A significant fusion defect was recapitulated in isolated myoblasts depleted of GRAF1 or its closely related family member GRAF2. Mechanistically, we show that GRAF1 and 2 facilitate myoblast fusion, at least in part, by promoting vesicle-mediated translocation of fusogenic ferlin proteins to the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GRAF1 promotes ferlin-dependent myoblast fusion

Lenhart

Becherer

et al. 2014

Developmental Biology

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“…Recent evidence also indicates a critical function for branched actin polymerization during Drosophila indirect flight muscle fusion (4). The essential role of the cytoskeleton in fusion is conserved in mammals, in which the actin regulators Rac1, cdc42, and N-WASp are required for muscle development (5)(6)(7)(8). In addition to actin dynamics, numerous proteins that regulate diverse cellular processes have been associated with myoblast fusion (9)(10)(11)(12)(13).…”

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confidence: 99%

Structure–function analysis of myomaker domains required for myoblast fusion

Millay

Gamage

Quinn

et al. 2016

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

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During skeletal muscle development, myoblasts fuse to form multinucleated myofibers. Myomaker [Transmembrane protein 8c (TMEM8c)] is a muscle-specific protein that is essential for myoblast fusion and sufficient to promote fusion of fibroblasts with muscle cells; however, the structure and biochemical properties of this membrane protein have not been explored. Here, we used CRISPR/Cas9 mutagenesis to disrupt myomaker expression in the C2C12 muscle cell line, which resulted in complete blockade to fusion. To define the functional domains of myomaker required to direct fusion, we established a heterologous cell-cell fusion system, in which fibroblasts expressing mutant versions of myomaker were mixed with WT myoblasts. Our data indicate that the majority of myomaker is embedded in the plasma membrane with seven membrane-spanning regions and a required intracellular C-terminal tail. We show that myomaker function is conserved in other mammalian orthologs; however, related family members (TMEM8a and TMEM8b) do not exhibit fusogenic activity. These findings represent an important step toward deciphering the cellular components and mechanisms that control myoblast fusion and muscle formation.P lasma membrane fusion is a fundamental cellular process required for the conception, development, and physiology of multicellular organisms. Membrane fusion occurs during viral infection of a host cell, between intracellular membranes, and between two plasma membranes to form syncytial tissues (1). Cell-cell fusion is critical for a wide array of cellular processes, including sperm-egg fertilization, macrophage function, bone and placental development, and skeletal muscle formation. This form of fusion must be precisely controlled to prevent inappropriate cellular mixing.The fusion of myoblasts requires cell recognition, migration, adhesion, signaling, and finally, membrane coalescence (2). Much of our knowledge about myoblast fusion has originated from studies performed in Drosophila. In this system, intracellular signaling results in cytoskeletal alterations and actin polymerization, which drive the formation of cellular projections that invade neighboring cells to cause fusion (3). Recent evidence also indicates a critical function for branched actin polymerization during Drosophila indirect flight muscle fusion (4). The essential role of the cytoskeleton in fusion is conserved in mammals, in which the actin regulators Rac1, cdc42, and N-WASp are required for muscle development (5-8). In addition to actin dynamics, numerous proteins that regulate diverse cellular processes have been associated with myoblast fusion (9-13).We recently discovered a muscle-specific membrane protein named myomaker [annotated as Transmembrane protein 8c (TMEM8c)] that is absolutely required for skeletal myocyte fusion in the mouse (14,15). To begin to decipher the mechanisms whereby myomaker controls cell-cell fusion, we designed a heterologous cell-cell fusion assay to monitor the ability of a series of myomaker mutants to direct the fusion of lab...

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“…Cultures were Ͼ95% myogenic as defined by MyoD immunostaining. Cells were cultured in growth media and switched to differentiation media (DM) for 24 or 40 -48 h as previously described (66). Experiments involving animals were performed in accordance with approved guidelines and ethical approval from Emory University's Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

“…N-BAR domain proteins, such as Bin3, link membrane dynamics to the actin cytoskeleton (21,57). In addition, we showed that Bin3 is important for lamellipodia formation and muscle cell motility, as well as myotube formation and growth (66). Small heat shock proteins, such as Hsbp3, inhibit actin polymerization by acting as capping proteins or may protect the actin cytoskeleton against disruption induced by various stressful conditions (42).…”

Section: Ckb Is Localized In Both Myocytes and Myotubesmentioning

confidence: 95%

Creatine kinase B is necessary to limit myoblast fusion during myogenesis

Simionescu-Bankston

Pichavant

Canner

et al. 2015

American Journal of Physiology-Cell Physiology

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GK.Creatine kinase B is necessary to limit myoblast fusion during myogenesis. Am J Physiol Cell Physiol 308: C919 -C931, 2015. First published March 25, 2015 doi:10.1152/ajpcell.00029.2015.-Myoblast fusion is critical for proper muscle growth and regeneration. During myoblast fusion, the localization of some molecules is spatially restricted; however, the exact reason for such localization is unknown. Creatine kinase B (CKB), which replenishes local ATP pools, localizes near the ends of cultured primary mouse myotubes. To gain insights into the function of CKB, we performed a yeast two-hybrid screen to identify CKB-interacting proteins. We identified molecules with a broad diversity of roles, including actin polymerization, intracellular protein trafficking, and alternative splicing, as well as sarcomeric components. In-depth studies of ␣-skeletal actin and ␣-cardiac actin, two predominant muscle actin isoforms, demonstrated their biochemical interaction and partial colocalization with CKB near the ends of myotubes in vitro. In contrast to other cell types, specific knockdown of CKB did not grossly affect actin polymerization in myotubes, suggesting other muscle-specific roles for CKB. Interestingly, knockdown of CKB resulted in significantly increased myoblast fusion and myotube size in vitro, whereas knockdown of creatine kinase M had no effect on these myogenic parameters. Our results suggest that localized CKB plays a key role in myotube formation by limiting myoblast fusion during myogenesis.

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The N-BAR domain protein, Bin3, regulates Rac1- and Cdc42-dependent processes in myogenesis

Cited by 28 publications

References 56 publications

GRAF1 promotes ferlin-dependent myoblast fusion

GRAF1 promotes ferlin-dependent myoblast fusion

Structure–function analysis of myomaker domains required for myoblast fusion

Creatine kinase B is necessary to limit myoblast fusion during myogenesis

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