title: Myoblasts and macrophages share molecular components that contribute to cell-cell fusion.
abstract: Cell-cell fusion is critical to the normal development of certain tissues, yet the nature and degree of conservation of the underlying molecular components remains largely unknown. Here we show that the two guanine-nucleotide exchange factors Brag2 and Dock180 have evolutionarily conserved functions in the fusion of mammalian myoblasts. Their effects on muscle cell formation are distinct and are a result of the activation of the GTPases ARF6 and Rac, respectively. Inhibition of ARF6 activity results in a lack of physical association between paxillin and beta(1)-integrin, and disruption of paxillin transport to sites of focal adhesion. We show that fusion machinery is conserved among distinct cell types because Dock180 deficiency prevented fusion of macrophages and the formation of multinucleated giant cells. Our results are the first to demonstrate a role for a single protein in the fusion of two different cell types, and provide novel mechanistic insight into the function of GEFs in the morphological maturation of multinucleated cells.
authors.affiliation: Department of Microbiology & Immunology, Baxter Laboratory in Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kostandin V
authors.initials: KV
authors.lastname: Pajcini
authors.forename: Jason H
authors.initials: JH
authors.lastname: Pomerantz
authors.forename: Ozan
authors.initials: O
authors.lastname: Alkan
authors.forename: Regis
authors.initials: R
authors.lastname: Doyonnas
authors.forename: Helen M
authors.initials: HM
authors.lastname: Blau
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002459:Cell Fusion; D002460:Cell Line; D022001:Focal Adhesions / Q000378:metabolism / Q000648:ultrastructure; D015726:Giant Cells / Q000378:metabolism* / Q000648:ultrastructure; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D032446:Myoblasts / Q000378:metabolism* / Q000648:ultrastructure; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D034741:RNA, Small Interfering; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D000089982:ADP-Ribosylation Factor 6; C493871:DOCK180 protein, rat; C528110:Dock180 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C504483:IQSEC1 protein, human; D019012:Integrin beta1; D009479:Neuropeptides; D051419:Paxillin; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein