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Molecular and Cellular Mechanisms of Mammalian Cell Fusion

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 713))

Abstract

The fusion of one cell with another occurs in development, injury and disease. Despite the diversity of fusion events, five steps in sequence appear common. These steps include programming fusion-competent status, chemotaxis, membrane adhesion, membrane fusion, and post-fusion resetting. Recent advances in the field start to reveal the molecules involved in each step. This review focuses on some key molecules and cellular events of cell fusion in mammals. Increasing evidence demonstrates that membrane lipid rafts, adhesion proteins and actin rearrangement are critical in the final step of membrane fusion. Here we propose a new model for the formation and expansion of membrane fusion pores based on recent observations on myotube formation. In this model, membrane lipid rafts first recruit adhesion molecules and align with opposing membranes, with the help of a cortical actin “wall” as a rigid supportive platform. Second, the membrane adhesion proteins interact with each other and trigger actin rearrangement, which leads to rapid dispersion of lipid rafts and flow of a highly fluidic phospholipid bilayer into the site. Finally, the opposing phospholipid bilayers are then pushed into direct contact leading to the formation of fusion pores by the force generated through actin polymerization. The actin polymerization generated force also drives the expansion of the fusion pores. However, several key questions about the process of cell fusion still remain to be explored. The understanding of the mechanisms of cell fusion may provide new opportunities in correcting development disorders or regenerating damaged tissues by inhibiting or promoting molecular events associated with fusion.

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References

  1. Schwann T (1839) Mikroskopische Untersuchungen uber die Uebereunstimmung in der Struktur und dem Wachsten der Thiere und Pflanzen. Sander’schen Buchhanlung, Berlin

    Google Scholar 

  2. Ogle BM, Cascalho M, Platt JL (2005) Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567–575

    PubMed  CAS  Google Scholar 

  3. Vjugina U, Evans JP (2008) New insights into the molecular basis of mammalian sperm-egg membrane interactions. Front Biosci 13:462–476

    PubMed  CAS  Google Scholar 

  4. Huppertz B, Bartz C, Kokozidou M (2006) Trophoblast fusion: fusogenic proteins, syncytins and ADAMs, and other prerequisites for syncytial fusion. Micron 37:509–517

    PubMed  CAS  Google Scholar 

  5. Rochlin K, Yu S, Roy S et al (2010) Myoblast fusion: when it takes more to make one. Dev Biol 341:66–83

    PubMed  CAS  Google Scholar 

  6. Helming L, Gordon S (2007) The molecular basis of macrophage fusion. Immunobiology 212:785–793

    PubMed  CAS  Google Scholar 

  7. Alvarez-Dolado M (2007) Cell fusion: biological perspectives and potential for regenerative medicine. Front Biosci 12:1–12

    PubMed  CAS  Google Scholar 

  8. Lluis F, Cosma MP (2010) Cell-fusion-mediated somatic-cell reprogramming: a mechanism for tissue regeneration. J Cell Physiol 223:6–13

    PubMed  CAS  Google Scholar 

  9. Helming L, Gordon S (2009) Molecular mediators of macrophage fusion. Trends Cell Biol 19:514–522

    PubMed  CAS  Google Scholar 

  10. DeFife KM, Jenney CR, McNally AK et al (1997) Interleukin-13 induces human monocyte/macrophage fusion and macrophage mannose receptor expression. J Immunol 158:3385–3390

    PubMed  CAS  Google Scholar 

  11. Enelow RI, Sullivan GW, Carper HT et al (1992) Induction of multinucleated giant cell formation from in vitro culture of human monocytes with interleukin-3 and interferon-gamma: comparison with other stimulating factors. Am J Respir Cell Mol Biol 6:57–62

    PubMed  CAS  Google Scholar 

  12. McNally AK, Anderson JM (1995) Interleukin-4 induces foreign body giant cells from human monocytes/macrophages. Differential lymphokine regulation of macrophage fusion leads to morphological variants of multinucleated giant cells. Am J Pathol 147:1487–1499

    PubMed  CAS  Google Scholar 

  13. Coury F, Annels N, Rivollier A et al (2008) Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion. Nat Med 14:81–87

    PubMed  CAS  Google Scholar 

  14. McInnes A, Rennick DM (1988) Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. J Exp Med 167:598–611

    PubMed  CAS  Google Scholar 

  15. Horsley V, Jansen KM, Mills ST et al (2003) IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113:483–494

    PubMed  CAS  Google Scholar 

  16. Weinberg JB, Hobbs MM, Misukonis MA (1984) Recombinant human gamma-interferon induces human monocyte polykaryon formation. Proc Natl Acad Sci USA 81:4554–4557

    PubMed  CAS  Google Scholar 

  17. Belosevic M, Finbloom DS, Van Der Meide PH et al (1989) Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol 143:266–274

    PubMed  CAS  Google Scholar 

  18. Chensue SW, Terebuh PD, Warmington KS et al (1992) Role of IL-4 and IFN-gamma in Schistosoma mansoni egg-induced hypersensitivity granuloma formation. Orchestration, relative contribution, and relationship to macrophage function. J Immunol 148:900–906

    PubMed  CAS  Google Scholar 

  19. Helming L, Gordon S (2007) Macrophage fusion induced by IL-4 alternative activation is a multistage process involving multiple target molecules. Eur J Immunol 37:33–42

    PubMed  CAS  Google Scholar 

  20. Moreno JL, Mikhailenko I, Tondravi MM et al (2007) IL-4 promotes the formation of multinucleated giant cells from macrophage precursors by a STAT6-dependent, homotypic mechanism: contribution of E-cadherin. J Leukoc Biol 82:1542–1553

    PubMed  CAS  Google Scholar 

  21. Van den Bossche J, Bogaert P, van Hengel J et al (2009) Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes. Blood 114:4664–4674

    PubMed  Google Scholar 

  22. Jones JA, McNally AK, Chang DT et al (2008) Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials. J Biomed Mater Res A 84:158–166

    PubMed  Google Scholar 

  23. MacLauchlan S, Skokos EA, Meznarich N et al (2009) Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9. J Leukoc Biol 85:617–626

    PubMed  CAS  Google Scholar 

  24. Yagi M, Ninomiya K, Fujita N et al (2007) Induction of DC-STAMP by alternative activation and downstream signaling mechanisms. J Bone Miner Res 22:992–1001

    PubMed  CAS  Google Scholar 

  25. Yagi M, Miyamoto T, Sawatani Y et al (2005) DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202:345–351

    PubMed  CAS  Google Scholar 

  26. Stein M, Keshav S, Harris N et al (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176:287–292

    PubMed  CAS  Google Scholar 

  27. McNally AK, DeFife KM, Anderson JM (1996) Interleukin-4-induced macrophage fusion is prevented by inhibitors of mannose receptor activity. Am J Pathol 149:975–985

    PubMed  CAS  Google Scholar 

  28. Jansen KM, Pavlath GK (2006) Mannose receptor regulates myoblast motility and muscle growth. J Cell Biol 174:403–413

    PubMed  CAS  Google Scholar 

  29. Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    PubMed  CAS  Google Scholar 

  30. Yasuda H, Shima N, Nakagawa N et al (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602

    PubMed  CAS  Google Scholar 

  31. Takayanagi H, Kim S, Koga T et al (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3:889–901

    PubMed  CAS  Google Scholar 

  32. Kim K, Lee SH, Ha Kim J et al (2008) NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol 22:176–185

    PubMed  CAS  Google Scholar 

  33. Feng H, Cheng T, Steer JH et al (2009) Myocyte enhancer factor 2 and microphthalmia-associated transcription factor cooperate with NFATc1 to transactivate the V-ATPase d2 promoter during RANKL-induced osteoclastogenesis. J Biol Chem 284:14667–14676

    PubMed  CAS  Google Scholar 

  34. Lee SH, Rho J, Jeong D et al (2006) v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med 12:1403–1409

    PubMed  CAS  Google Scholar 

  35. Simonet WS, Lacey DL, Dunstan CR et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    PubMed  CAS  Google Scholar 

  36. Yasuda H, Shima N, Nakagawa N et al (1998) Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139:1329–1337

    PubMed  Google Scholar 

  37. Helming L, Tomasello E, Kyriakides TR et al (2008) Essential role of DAP12 signaling in macrophage programming into a fusion-competent state. Sci Signal 1:ra11

    PubMed  Google Scholar 

  38. Paloneva J, Mandelin J, Kiialainen A et al (2003) DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med 198:669–675

    PubMed  CAS  Google Scholar 

  39. Kaifu T, Nakahara J, Inui M et al (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332

    PubMed  CAS  Google Scholar 

  40. Peng Q, Malhotra S, Torchia JA et al (2010) TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal 3:ra38

    PubMed  Google Scholar 

  41. Turnbull IR, Colonna M (2007) Activating and inhibitory functions of DAP12. Nat Rev Immunol 7:155–161

    PubMed  CAS  Google Scholar 

  42. Zou W, Reeve JL, Liu Y et al (2008) DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol Cell 31:422–431

    PubMed  CAS  Google Scholar 

  43. Sessions A, Horwitz AF (1983) Differentiation-related differences in the plasma membrane phospholipid asymmetry of myogenic and fibrogenic cells. Biochim Biophys Acta 728:103–111

    PubMed  CAS  Google Scholar 

  44. Adler RR, Ng AK, Rote NS (1995) Monoclonal antiphosphatidylserine antibody inhibits intercellular fusion of the choriocarcinoma line, JAR. Biol Reprod 53:905–910

    PubMed  CAS  Google Scholar 

  45. Gadella BM, Harrison RA (2000) The capacitating agent bicarbonate induces protein kinase A-dependent changes in phospholipid transbilayer behavior in the sperm plasma membrane. Development 127:2407–2420

    PubMed  CAS  Google Scholar 

  46. Helming L, Winter J, Gordon S (2009) The scavenger receptor CD36 plays a role in cytokine-induced macrophage fusion. J Cell Sci 122:453–459

    PubMed  CAS  Google Scholar 

  47. Leventis PA, Grinstein S (2010) The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 39:407–427

    PubMed  CAS  Google Scholar 

  48. Gauster M, Huppertz B (2010) The paradox of caspase 8 in human villous trophoblast fusion. Placenta 31:82–88

    PubMed  CAS  Google Scholar 

  49. Rote NS, Wei BR, Xu C et al (2010) Caspase 8 and human villous cytotrophoblast differentiation. Placenta 31:89–96

    PubMed  CAS  Google Scholar 

  50. Harrison RA, Gadella BM (2005) Bicarbonate-induced membrane processing in sperm capacitation. Theriogenology 63:342–351

    PubMed  CAS  Google Scholar 

  51. Gadella BM, Harrison RA (2002) Capacitation induces cyclic adenosine 3,5-monophosphate-dependent, but apoptosis-unrelated, exposure of aminophospholipids at the apical head plasma membrane of boar sperm cells. Biol Reprod 67:340–350

    PubMed  CAS  Google Scholar 

  52. Flesch FM, Brouwers JF, Nievelstein PF et al (2001) Bicarbonate stimulated phospholipid scrambling induces cholesterol redistribution and enables cholesterol depletion in the sperm plasma membrane. J Cell Sci 114:3543–3555

    PubMed  CAS  Google Scholar 

  53. Harrison RA, Ashworth PJ, Miller NG (1996) Bicarbonate/CO2, an effector of capacitation, induces a rapid and reversible change in the lipid architecture of boar sperm plasma membranes. Mol Reprod Dev 45:378–391

    PubMed  CAS  Google Scholar 

  54. Litvin TN, Kamenetsky M, Zarifyan A et al (2003) Kinetic properties of “soluble” adenylyl cyclase. Synergism between calcium and bicarbonate. J Biol Chem 278:15922–15926

    PubMed  CAS  Google Scholar 

  55. Harrison RA, Miller NG (2000) cAMP-dependent protein kinase control of plasma membrane lipid architecture in boar sperm. Mol Reprod Dev 55:220–228

    PubMed  CAS  Google Scholar 

  56. Harrison RA (1996) Capacitation mechanisms, and the role of capacitation as seen in eutherian mammals. Reprod Fertil Dev 8:581–594

    PubMed  CAS  Google Scholar 

  57. de Vries KJ, Wiedmer T, Sims PJ et al (2003) Caspase-independent exposure of aminophospholipids and tyrosine phosphorylation in bicarbonate responsive human sperm cells. Biol Reprod 68:2122–2134

    PubMed  Google Scholar 

  58. Callahan MK, Williamson P, Schlegel RA (2000) Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes. Cell Death Differ 7:645–653

    PubMed  CAS  Google Scholar 

  59. MacKenzie A, Wilson HL, Kiss-Toth E et al (2001) Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity 15:825–835

    PubMed  CAS  Google Scholar 

  60. Van den Eijnde SM, Boshart L, Reutelingsperger CP et al (1997) Phosphatidylserine plasma membrane asymmetry in vivo: a pancellular phenomenon which alters during apoptosis. Cell Death Differ 4:311–316

    PubMed  Google Scholar 

  61. van den Eijnde SM, van den Hoff MJ, Reutelingsperger CP et al (2001) Transient expression of phosphatidylserine at cell-cell contact areas is required for myotube formation. J Cell Sci 114:3631–3642

    PubMed  Google Scholar 

  62. Lyden TW, Vogt E, Ng AK et al (1992) Monoclonal antiphospholipid antibody reactivity against human placental trophoblast. J Reprod Immunol 22:1–14

    PubMed  CAS  Google Scholar 

  63. Lyden TW, Ng AK, Rote NS (1993) Modulation of phosphatidylserine epitope expression by BeWo cells during forskolin treatment. Placenta 14:177–186

    PubMed  CAS  Google Scholar 

  64. Vogt E, Ng AK, Rote NS (1996) A model for the antiphospholipid antibody syndrome: monoclonal antiphosphatidylserine antibody induces intrauterine growth restriction in mice. Am J Obstet Gynecol 174:700–707

    PubMed  CAS  Google Scholar 

  65. Daleke DL (2007) Phospholipid flippases. J Biol Chem 282:821–825

    PubMed  CAS  Google Scholar 

  66. Florman HM, Jungnickel MK, Sutton KA (2008) Regulating the acrosome reaction. Int J Dev Biol 52:503–510

    PubMed  CAS  Google Scholar 

  67. Wassarman PM, Litscher ES (2008) Mammalian fertilization is dependent on multiple membrane fusion events. Methods Mol Biol 475:99–113

    PubMed  Google Scholar 

  68. Inoue N, Ikawa M, Isotani A et al (2005) The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature 434:234–238

    PubMed  CAS  Google Scholar 

  69. Myles DG, Koppel DE, Cowan AE et al (1987) Rearrangement of sperm surface antigens prior to fertilization. Ann N Y Acad Sci 513:262–273

    PubMed  CAS  Google Scholar 

  70. Miranda PV, Allaire A, Sosnik J et al (2009) Localization of low-density detergent-resistant membrane proteins in intact and acrosome-reacted mouse sperm. Biol Reprod 80:897–904

    PubMed  CAS  Google Scholar 

  71. Sosnik J, Miranda PV, Spiridonov NA et al (2009) Tssk6 is required for Izumo relocalization and gamete fusion in the mouse. J Cell Sci 122:2741–2749

    PubMed  CAS  Google Scholar 

  72. Bleil JD, Wassarman PM (1983) Sperm–egg interactions in the mouse: sequence of events and induction of the acrosome reaction by a zona pellucida glycoprotein. Dev Biol 95:317–324

    PubMed  CAS  Google Scholar 

  73. Arnoult C, Zeng Y, Florman HM (1996) ZP3-dependent activation of sperm cation channels regulates acrosomal secretion during mammalian fertilization. J Cell Biol 134:637–645

    PubMed  CAS  Google Scholar 

  74. Florman HM, Tombes RM, First NL et al (1989) An adhesion-associated agonist from the zona pellucida activates G protein-promoted elevations of internal Ca2+ and pH that mediate mammalian sperm acrosomal exocytosis. Dev Biol 135:133–146

    PubMed  CAS  Google Scholar 

  75. Arnoult C, Cardullo RA, Lemos JR et al (1996) Activation of mouse sperm T-type Ca2+ channels by adhesion to the egg zona pellucida. Proc Natl Acad Sci USA 93:13004–13009

    PubMed  CAS  Google Scholar 

  76. Fukami K, Nakao K, Inoue T et al (2001) Requirement of phospholipase Cdelta4 for the zona pellucida-induced acrosome reaction. Science 292:920–923

    PubMed  CAS  Google Scholar 

  77. Fukami K, Yoshida M, Inoue T et al (2003) Phospholipase Cdelta4 is required for Ca2+ mobilization essential for acrosome reaction in sperm. J Cell Biol 161:79–88

    PubMed  CAS  Google Scholar 

  78. Jungnickel MK, Sutton KA, Wang Y et al (2007) Phosphoinositide-dependent pathways in mouse sperm are regulated by egg ZP3 and drive the acrosome reaction. Dev Biol 304:116–126

    PubMed  CAS  Google Scholar 

  79. Achuthan A, Masendycz P, Lopez JA et al (2008) Regulation of the endosomal SNARE protein syntaxin 7 by colony-stimulating factor 1 in macrophages. Mol Cell Biol 28:6149–6159

    PubMed  CAS  Google Scholar 

  80. Tomes CN, De Blas GA, Michaut MA et al (2005) alpha-SNAP and NSF are required in a priming step during the human sperm acrosome reaction. Mol Hum Reprod 11:43–51

    PubMed  CAS  Google Scholar 

  81. Tomes CN, Michaut M, De Blas G et al (2002) SNARE complex assembly is required for human sperm acrosome reaction. Dev Biol 243:326–338

    PubMed  CAS  Google Scholar 

  82. Lamkanfi M, Festjens N, Declercq W et al (2007) Caspases in cell survival, proliferation and differentiation. Cell Death Differ 14:44–55

    PubMed  CAS  Google Scholar 

  83. Black S, Kadyrov M, Kaufmann P et al (2004) Syncytial fusion of human trophoblast depends on caspase 8. Cell Death Differ 11:90–98

    PubMed  CAS  Google Scholar 

  84. Gauster M, Siwetz M, Orendi K et al (2010) Caspases rather than calpains mediate remodelling of the fodrin skeleton during human placental trophoblast fusion. Cell Death Differ 17:336–345

    PubMed  CAS  Google Scholar 

  85. Martens S, McMahon HT (2008) Mechanisms of membrane fusion: disparate players and common principles. Nat Rev Mol Cell Biol 9:543–556

    PubMed  CAS  Google Scholar 

  86. Mandal D, Mazumder A, Das P et al (2005) Fas-, caspase 8-, and caspase 3-dependent signaling regulates the activity of the aminophospholipid translocase and phosphatidylserine externalization in human erythrocytes. J Biol Chem 280:39460–39467

    PubMed  CAS  Google Scholar 

  87. Gauster M, Siwetz M, Huppertz B (2009) Fusion of villous trophoblast can be visualized by localizing active caspase 8. Placenta 30:547–550

    PubMed  CAS  Google Scholar 

  88. Murray TV, McMahon JM, Howley BA et al (2008) A non-apoptotic role for caspase-9 in muscle differentiation. J Cell Sci 121:3786–3793

    PubMed  CAS  Google Scholar 

  89. Fernando P, Kelly JF, Balazsi K et al (2002) Caspase 3 activity is required for skeletal muscle differentiation. Proc Natl Acad Sci USA 99:11025–11030

    PubMed  CAS  Google Scholar 

  90. Goll DE, Thompson VF, Li H et al (2003) The calpain system. Physiol Rev 83:731–801

    PubMed  CAS  Google Scholar 

  91. Balcerzak D, Poussard S, Brustis JJ et al (1995) An antisense oligodeoxyribonucleotide to m-calpain mRNA inhibits myoblast fusion. J Cell Sci 108 (Pt 5):2077–2082

    PubMed  CAS  Google Scholar 

  92. Kuchay SM, Kim N, Grunz EA et al (2007) Double knockouts reveal that protein tyrosine phosphatase 1B is a physiological target of calpain-1 in platelets. Mol Cell Biol 27:6038–6052

    PubMed  CAS  Google Scholar 

  93. Honda M, Masui F, Kanzawa N et al (2008) Specific knockdown of m-calpain blocks myogenesis with cDNA deduced from the corresponding RNAi. Am J Physiol Cell Physiol 294:C957–965

    Google Scholar 

  94. Kramerova I, Kudryashova E, Tidball JG et al (2004) Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum Mol Genet 13:1373–1388

    PubMed  CAS  Google Scholar 

  95. Kramerova I, Kudryashova E, Wu B et al (2006) Regulation of the M-cadherin-beta-catenin complex by calpain 3 during terminal stages of myogenic differentiation. Mol Cell Biol 26:8437–8447

    PubMed  CAS  Google Scholar 

  96. Charrasse S, Comunale F, Grumbach Y et al (2006) RhoA GTPase regulates M-cadherin activity and myoblast fusion. Mol Biol Cell 17:749–759

    PubMed  CAS  Google Scholar 

  97. Kim YS, Nakanishi G, Lewandoski M et al (2003) GLIS3, a novel member of the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and activation functions. Nucleic Acids Res 31:5513–5525

    PubMed  CAS  Google Scholar 

  98. Duan H, Nguyen HT (2006) Distinct posttranscriptional mechanisms regulate the activity of the Zn finger transcription factor lame duck during Drosophila myogenesis. Mol Cell Biol 26:1414–1423

    PubMed  CAS  Google Scholar 

  99. Duan H, Skeath JB, Nguyen HT (2001) Drosophila Lame duck, a novel member of the Gli superfamily, acts as a key regulator of myogenesis by controlling fusion-competent myoblast development. Development 128:4489–4500

    PubMed  CAS  Google Scholar 

  100. Furlong EE, Andersen EC, Null B et al (2001) Patterns of gene expression during Drosophila mesoderm development. Science 293:1629–1633

    PubMed  CAS  Google Scholar 

  101. Ruiz-Gomez M, Coutts N, Suster ML et al (2002) myoblasts incompetent encodes a zinc finger transcription factor required to specify fusion-competent myoblasts in Drosophila. Development 129:133–141

    PubMed  CAS  Google Scholar 

  102. Watanabe N, Hiramatsu K, Miyamoto R et al (2009) A murine model of neonatal diabetes mellitus in Glis3-deficient mice. FEBS Lett 583:2108–2113

    PubMed  CAS  Google Scholar 

  103. Kang HS, Kim YS, ZeRuth G et al (2009) Transcription factor Glis3, a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression. Mol Cell Biol 29:6366–6379

    PubMed  CAS  Google Scholar 

  104. Brand-Saberi B, Muller TS, Wilting J et al (1996) Scatter factor/hepatocyte growth factor (SF/HGF) induces emigration of myogenic cells at interlimb level in vivo. Dev Biol 179:303–308

    PubMed  CAS  Google Scholar 

  105. Corti S, Salani S, Del Bo R et al (2001) Chemotactic factors enhance myogenic cell migration across an endothelial monolayer. Exp Cell Res 268:36–44

    PubMed  CAS  Google Scholar 

  106. Lafreniere JF, Mills P, Bouchentouf M et al (2006) Interleukin-4 improves the migration of human myogenic precursor cells in vitro and in vivo. Exp Cell Res 312:1127–1141

    PubMed  CAS  Google Scholar 

  107. Lafreniere JF, Mills P, Tremblay JP et al (2004) Growth factors improve the in vivo migration of human skeletal myoblasts by modulating their endogenous proteolytic activity. Transplantation 77:1741–1747

    PubMed  CAS  Google Scholar 

  108. Webb SE, Lee KK, Tang MK et al (1997) Fibroblast growth factors 2 and 4 stimulate migration of mouse embryonic limb myogenic cells. Dev Dyn 209:206–216

    PubMed  CAS  Google Scholar 

  109. Robertson TA, Maley MA, Grounds MD et al (1993) The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res 207:321–331

    PubMed  CAS  Google Scholar 

  110. Minniti CP, Luan D, O‘Grady C et al (1995) Insulin-like growth factor II overexpression in myoblasts induces phenotypic changes typical of the malignant phenotype. Cell Growth Differ 6:263–269

    PubMed  CAS  Google Scholar 

  111. Germani A, Di Carlo A, Mangoni A et al (2003) Vascular endothelial growth factor modulates skeletal myoblast function. Am J Pathol 163:1417–1428

    PubMed  CAS  Google Scholar 

  112. Ratajczak MZ, Majka M, Kucia M et al (2003) Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells 21:363–371

    PubMed  CAS  Google Scholar 

  113. Allen DL, Teitelbaum DH, Kurachi K (2003) Growth factor stimulation of matrix metalloproteinase expression and myoblast migration and invasion in vitro. Am J Physiol Cell Physiol 284:C805–815

    Google Scholar 

  114. Torrente Y, El Fahime E, Caron NJ et al (2003) Tumor necrosis factor-alpha (TNF-alpha) stimulates chemotactic response in mouse myogenic cells. Cell Transplant 12:91–100

    PubMed  CAS  Google Scholar 

  115. Chowdhury SR, Muneyuki Y, Takezawa Y et al (2009) Synergic stimulation of laminin and epidermal growth factor facilitates the myoblast growth through promoting migration. J Biosci Bioeng 108:174–177

    PubMed  CAS  Google Scholar 

  116. Adams JC, Schwartz MA (2000) Stimulation of fascin spikes by thrombospondin-1 is mediated by the GTPases Rac and Cdc42. J Cell Biol 150:807–822

    PubMed  CAS  Google Scholar 

  117. Turner DC, Lawton J, Dollenmeier P et al (1983) Guidance of myogenic cell migration by oriented deposits of fibronectin. Dev Biol 95:497–504

    PubMed  CAS  Google Scholar 

  118. Yao CC, Ziober BL, Sutherland AE et al (1996) Laminins promote the locomotion of skeletal myoblasts via the alpha 7 integrin receptor. J Cell Sci 109 (Pt 13):3139–3150

    PubMed  CAS  Google Scholar 

  119. Bischoff R (1997) Chemotaxis of skeletal muscle satellite cells. Dev Dyn 208:505–515

    PubMed  CAS  Google Scholar 

  120. Rosario M, Birchmeier W (2003) How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol 13:328–335

    PubMed  CAS  Google Scholar 

  121. Odemis V, Lamp E, Pezeshki G et al (2005) Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Mol Cell Neurosci 30:494–505

    PubMed  Google Scholar 

  122. Forde S, Tye BJ, Newey SE et al (2007) Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells. Blood 109:1825–1833

    PubMed  CAS  Google Scholar 

  123. Bae GU, Gaio U, Yang YJ et al (2008) Regulation of myoblast motility and fusion by the CXCR4-associated sialomucin, CD164. J Biol Chem 283:8301–8309

    PubMed  CAS  Google Scholar 

  124. Miller RJ, Banisadr G, Bhattacharyya BJ (2008) CXCR4 signaling in the regulation of stem cell migration and development. J Neuroimmunol 198:31–38

    PubMed  CAS  Google Scholar 

  125. Nagasawa T (2007) The chemokine CXCL12 and regulation of HSC and B lymphocyte development in the bone marrow niche. Adv Exp Med Biol 602:69–75

    PubMed  Google Scholar 

  126. Lazarini F, Tham TN, Casanova P et al (2003) Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia 42:139–148

    PubMed  Google Scholar 

  127. Stumm RK, Rummel J, Junker V et al (2002) A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci 22:5865–5878

    PubMed  CAS  Google Scholar 

  128. Yamaguchi J, Kusano KF, Masuo O et al (2003) Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107:1322–1328

    PubMed  CAS  Google Scholar 

  129. Fox JM, Chamberlain G, Ashton BA et al (2007) Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol 137:491–502

    PubMed  CAS  Google Scholar 

  130. Hill WD, Hess DC, Martin-Studdard A et al (2004) SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol 63:84–96

    PubMed  CAS  Google Scholar 

  131. Togel F, Isaac J, Hu Z et al (2005) Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int 67:1772–1784

    PubMed  Google Scholar 

  132. Blanchet MR, McNagny KM (2009) Stem cells, inflammation and allergy. Allergy Asthma Clin Immunol 5:13

    PubMed  Google Scholar 

  133. Kucia M, Ratajczak J, Reca R et al (2004) Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury. Blood Cells Mol Dis 32:52–57

    PubMed  CAS  Google Scholar 

  134. Davies PS, Powell AE, Swain JR et al (2009) Inflammation and proliferation act together to mediate intestinal cell fusion. PLoS ONE 4:e6530

    PubMed  Google Scholar 

  135. Nygren JM, Liuba K, Breitbach M et al (2008) Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat Cell Biol 10:584–592

    PubMed  CAS  Google Scholar 

  136. Johansson CB, Youssef S, Koleckar K et al (2008) Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol 10:575–583

    PubMed  CAS  Google Scholar 

  137. Horsley V, Friday BB, Matteson S et al (2001) Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway. J Cell Biol 153:329–338

    PubMed  CAS  Google Scholar 

  138. Sotiropoulos A, Ohanna M, Kedzia C et al (2006) Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc Natl Acad Sci USA 103:7315–7320

    PubMed  CAS  Google Scholar 

  139. Griffin CA, Kafadar KA, Pavlath GK (2009) MOR23 promotes muscle regeneration and regulates cell adhesion and migration. Dev Cell 17:649–661

    PubMed  CAS  Google Scholar 

  140. Fukuda N, Yomogida K, Okabe M et al (2004) Functional characterization of a mouse testicular olfactory receptor and its role in chemosensing and in regulation of sperm motility. J Cell Sci 117:5835–5845

    PubMed  CAS  Google Scholar 

  141. Tangirala RK, Murao K, Quehenberger O (1997) Regulation of expression of the human monocyte chemotactic protein-1 receptor (hCCR2) by cytokines. J Biol Chem 272:8050–8056

    PubMed  CAS  Google Scholar 

  142. Kyriakides TR, Foster MJ, Keeney GE et al (2004) The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation. Am J Pathol 165:2157–2166

    PubMed  CAS  Google Scholar 

  143. Jay SM, Skokos E, Laiwalla F et al (2007) Foreign body giant cell formation is preceded by lamellipodia formation and can be attenuated by inhibition of Rac1 activation. Am J Pathol 171:632–640

    PubMed  CAS  Google Scholar 

  144. Miyamoto K, Ninomiya K, Sonoda KH et al (2009) MCP-1 expressed by osteoclasts stimulates osteoclastogenesis in an autocrine/paracrine manner. Biochem Biophys Res Commun 383:373–377

    PubMed  CAS  Google Scholar 

  145. Harper CV, Barratt CL, Publicover SJ (2004) Stimulation of human spermatozoa with progesterone gradients to simulate approach to the oocyte. Induction of [Ca(2+)](i) oscillations and cyclical transitions in flagellar beating. J Biol Chem 279:46315–46325

    PubMed  CAS  Google Scholar 

  146. Teves ME, Barbano F, Guidobaldi HA et al (2006) Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa. Fertil Steril 86:745–749

    PubMed  CAS  Google Scholar 

  147. Teves ME, Guidobaldi HA, Unates DR et al (2010) Progesterone sperm chemoattraction may be modulated by its corticosteroid-binding globulin carrier protein. Fertil Steril 93:2450–2452

    PubMed  CAS  Google Scholar 

  148. Teves ME, Guidobaldi HA, Unates DR et al (2009) Molecular mechanism for human sperm chemotaxis mediated by progesterone. PLoS ONE 4:e8211

    PubMed  Google Scholar 

  149. Osman RA, Andria ML, Jones AD et al (1989) Steroid induced exocytosis: the human sperm acrosome reaction. Biochem Biophys Res Commun 160:828–833

    PubMed  CAS  Google Scholar 

  150. Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2:91–100

    PubMed  Google Scholar 

  151. Ocalan M, Goodman SL, Kuhl U et al (1988) Laminin alters cell shape and stimulates motility and proliferation of murine skeletal myoblasts. Dev Biol 125:158–167

    PubMed  CAS  Google Scholar 

  152. Sonnenberg A, Modderman PW, Hogervorst F (1988) Laminin receptor on platelets is the integrin VLA-6. Nature 336:487–489

    PubMed  CAS  Google Scholar 

  153. Kramer RH, McDonald KA, Vu MP (1989) Human melanoma cells express a novel integrin receptor for laminin. J Biol Chem 264:15642–15649

    PubMed  CAS  Google Scholar 

  154. Siegel AL, Atchison K, Fisher KE et al (2009) 3D timelapse analysis of muscle satellite cell motility. Stem Cells 27:2527–2538

    PubMed  CAS  Google Scholar 

  155. Mayer U, Saher G, Fassler R et al (1997) Absence of integrin alpha 7 causes a novel form of muscular dystrophy. Nat Genet 17:318–323

    PubMed  CAS  Google Scholar 

  156. Schwander M, Leu M, Stumm M et al (2003) Beta1 integrins regulate myoblast fusion and sarcomere assembly. Dev Cell 4:673–685

    PubMed  CAS  Google Scholar 

  157. Echtermeyer F, Schober S, Poschl E et al (1996) Specific induction of cell motility on laminin by alpha 7 integrin. J Biol Chem 271:2071–2075

    PubMed  CAS  Google Scholar 

  158. Glenn HL, Wang Z, Schwartz LM (2010) Acheron, a Lupus antigen family member, regulates integrin expression, adhesion, and motility in differentiating myoblasts. Am J Physiol Cell Physiol 298:C46–55

    Google Scholar 

  159. Wang Z, Glenn H, Brown C et al (2009) Regulation of muscle differentiation and survival by Acheron. Mech Dev 126:700–709

    PubMed  CAS  Google Scholar 

  160. Calderwood DA, Shattil SJ, Ginsberg MH (2000) Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling. J Biol Chem 275:22607–22610

    PubMed  CAS  Google Scholar 

  161. Alvarez B, Stroeken PJ, Edel MJ et al (2008) Integrin Cytoplasmic domain-Associated Protein-1 (ICAP-1) promotes migration of myoblasts and affects focal adhesions. J Cell Physiol 214:474–482

    PubMed  CAS  Google Scholar 

  162. Boissy P, Machuca I, Pfaff M et al (1998) Aggregation of mononucleated precursors triggers cell surface expression of alphavbeta3 integrin, essential to formation of osteoclast-like multinucleated cells. J Cell Sci 111(Pt 17):2563–2574

    PubMed  CAS  Google Scholar 

  163. McHugh KP, Hodivala-Dilke K, Zheng MH et al (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105:433–440

    PubMed  CAS  Google Scholar 

  164. Lakkakorpi PT, Bett AJ, Lipfert L et al (2003) PYK2 autophosphorylation, but not kinase activity, is necessary for adhesion-induced association with c-Src, osteoclast spreading, and bone resorption. J Biol Chem 278:11502–11512

    PubMed  CAS  Google Scholar 

  165. Miyazaki T, Sanjay A, Neff L et al (2004) Src kinase activity is essential for osteoclast function. J Biol Chem 279:17660–17666

    PubMed  CAS  Google Scholar 

  166. Brazier H, Pawlak G, Vives V et al (2009) The Rho GTPase Wrch1 regulates osteoclast precursor adhesion and migration. Int J Biochem Cell Biol 41:1391–1401

    PubMed  CAS  Google Scholar 

  167. Brazier H, Stephens S, Ory S et al (2006) Expression profile of RhoGTPases and RhoGEFs during RANKL-stimulated osteoclastogenesis: identification of essential genes in osteoclasts. J Bone Miner Res 21:1387–1398

    PubMed  CAS  Google Scholar 

  168. Kim T, Ha HI, Kim N et al (2009) Adrm1 interacts with Atp6v0d2 and regulates osteoclast differentiation. Biochem Biophys Res Commun 390:585–590

    PubMed  CAS  Google Scholar 

  169. Husnjak K, Elsasser S, Zhang N et al (2008) Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453:481–488

    PubMed  CAS  Google Scholar 

  170. Stricker J, Falzone T, Gardel ML (2010) Mechanics of the F-actin cytoskeleton. J Biomech 43:9–14

    PubMed  Google Scholar 

  171. Nowak SJ, Nahirney PC, Hadjantonakis AK et al (2009) Nap1-mediated actin remodeling is essential for mammalian myoblast fusion. J Cell Sci 122:3282–3293

    PubMed  CAS  Google Scholar 

  172. Kawamura K, Takano K, Suetsugu S et al (2004) N-WASP and WAVE2 acting downstream of phosphatidylinositol 3-kinase are required for myogenic cell migration induced by hepatocyte growth factor. J Biol Chem 279:54862–54871

    PubMed  CAS  Google Scholar 

  173. Vasyutina E, Martarelli B, Brakebusch C et al (2009) The small G-proteins Rac1 and Cdc42 are essential for myoblast fusion in the mouse. Proc Natl Acad Sci USA 106:8935–8940

    PubMed  CAS  Google Scholar 

  174. Wells CM, Walmsley M, Ooi S et al (2004) Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci 117:1259–1268

    PubMed  CAS  Google Scholar 

  175. Wheeler AP, Wells CM, Smith SD et al (2006) Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. J Cell Sci 119:2749–2757

    PubMed  CAS  Google Scholar 

  176. Rohatgi R, Ho HY, Kirschner MW (2000) Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate. J Cell Biol 150:1299–1310

    PubMed  CAS  Google Scholar 

  177. Morishima S, Morita I, Tokushima T et al (2003) Expression and role of mannose receptor/terminal high-mannose type oligosaccharide on osteoclast precursors during osteoclast formation. J Endocrinol 176:285–292

    PubMed  CAS  Google Scholar 

  178. Taylor ME, Bezouska K, Drickamer K (1992) Contribution to ligand binding by multiple carbohydrate-recognition domains in the macrophage mannose receptor. J Biol Chem 267:1719–1726

    PubMed  CAS  Google Scholar 

  179. Chabot V, Reverdiau P, Iochmann S et al (2006) CCL5-enhanced human immature dendritic cell migration through the basement membrane in vitro depends on matrix metalloproteinase-9. J Leukoc Biol 79:767–778

    PubMed  CAS  Google Scholar 

  180. Rahat MA, Marom B, Bitterman H et al (2006) Hypoxia reduces the output of matrix metalloproteinase-9 (MMP-9) in monocytes by inhibiting its secretion and elevating membranal association. J Leukoc Biol 79:706–718

    PubMed  CAS  Google Scholar 

  181. Barclay AN (2003) Membrane proteins with immunoglobulin-like domains–a master superfamily of interaction molecules. Semin Immunol 15:215–223

    PubMed  CAS  Google Scholar 

  182. Xu Z, Jin B (2010) A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions. Cell Mol Immunol 7:11–19

    PubMed  Google Scholar 

  183. Sohn RL, Huang P, Kawahara G et al (2009) A role for nephrin, a renal protein, in vertebrate skeletal muscle cell fusion. Proc Natl Acad Sci USA 106:9274–9279

    PubMed  CAS  Google Scholar 

  184. Donoviel DB, Freed DD, Vogel H et al (2001) Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol 21:4829–4836

    PubMed  CAS  Google Scholar 

  185. Garg P, Verma R, Nihalani D et al (2007) Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol 27:8698–8712

    PubMed  CAS  Google Scholar 

  186. Krauss RS (2010) Regulation of promyogenic signal transduction by cell-cell contact and adhesion. Exp Cell Res 316:3042–3049

    Google Scholar 

  187. Lu M, Krauss RS (2010) N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38alpha/beta MAPK signaling in skeletal myoblasts. Proc Natl Acad Sci USA 107:4212–4217

    PubMed  CAS  Google Scholar 

  188. Kang JS, Bae GU, Yi MJ et al (2008) A Cdo-Bnip-2-Cdc42 signaling pathway regulates p38alpha/beta MAPK activity and myogenic differentiation. J Cell Biol 182:497–507

    PubMed  CAS  Google Scholar 

  189. Guasconi V, Puri PL (2009) Chromatin: the interface between extrinsic cues and the epigenetic regulation of muscle regeneration. Trends Cell Biol 19:286–294

    PubMed  CAS  Google Scholar 

  190. Takaesu G, Kang JS, Bae GU et al (2006) Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP to the cell surface protein Cdo. J Cell Biol 175:383–388

    PubMed  CAS  Google Scholar 

  191. Cole F, Zhang W, Geyra A et al (2004) Positive regulation of myogenic bHLH factors and skeletal muscle development by the cell surface receptor CDO. Dev Cell 7:843–854

    PubMed  CAS  Google Scholar 

  192. Bae GU, Yang YJ, Jiang G et al (2009) Neogenin regulates skeletal myofiber size and focal adhesion kinase and extracellular signal-regulated kinase activities in vivo and in vitro. Mol Biol Cell 20:4920–4931

    PubMed  CAS  Google Scholar 

  193. De Vries M, Cooper HM (2008) Emerging roles for neogenin and its ligands in CNS development. J Neurochem 106:1483–1492

    PubMed  Google Scholar 

  194. Quach NL, Biressi S, Reichardt LF et al (2009) Focal adhesion kinase signaling regulates the expression of caveolin 3 and beta1 integrin, genes essential for normal myoblast fusion. Mol Biol Cell 20:3422–3435

    PubMed  CAS  Google Scholar 

  195. Dickson G, Gower HJ, Barton CH et al (1987) Human muscle neural cell adhesion molecule (N-CAM): identification of a muscle-specific sequence in the extracellular domain. Cell 50:1119–1130

    PubMed  CAS  Google Scholar 

  196. Povlsen GK, Ditlevsen DK (2010) The neural cell adhesion molecule NCAM and lipid rafts. Adv Exp Med Biol 663:183–198

    PubMed  CAS  Google Scholar 

  197. Dickson G, Peck D, Moore SE et al (1990) Enhanced myogenesis in NCAM-transfected mouse myoblasts. Nature 344:348–351

    PubMed  CAS  Google Scholar 

  198. Baldwin TJ, Fazeli MS, Doherty P et al (1996) Elucidation of the molecular actions of NCAM and structurally related cell adhesion molecules. J Cell Biochem 61:502–513

    PubMed  CAS  Google Scholar 

  199. Charlton CA, Mohler WA, Blau HM (2000) Neural cell adhesion molecule (NCAM) and myoblast fusion. Developmental Biology 221:112–119

    PubMed  CAS  Google Scholar 

  200. Okabe M, Adachi T, Takada K et al (1987) Capacitation-related changes in antigen distribution on mouse sperm heads and its relation to fertilization rate in vitro. J Reprod Immunol 11:91–100

    PubMed  CAS  Google Scholar 

  201. Ellerman DA, Pei J, Gupta S et al (2009) Izumo is part of a multiprotein family whose members form large complexes on mammalian sperm. Mol Reprod Dev 76:1188–1199

    PubMed  CAS  Google Scholar 

  202. Lundberg P, Koskinen C, Baldock PA et al (2007) Osteoclast formation is strongly reduced both in vivo and in vitro in the absence of CD47/SIRPalpha-interaction. Biochem Biophys Res Commun 352:444–448

    PubMed  CAS  Google Scholar 

  203. Han X, Sterling H, Chen Y et al (2000) CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation. J Biol Chem 275:37984–37992

    PubMed  CAS  Google Scholar 

  204. Saginario C, Qian HY, Vignery A (1995) Identification of an inducible surface molecule specific to fusing macrophages. Proc Natl Acad Sci USA 92:12210–12214

    PubMed  CAS  Google Scholar 

  205. Matozaki T, Murata Y, Okazawa H et al (2009) Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol 19:72–80

    PubMed  CAS  Google Scholar 

  206. Oldenborg PA, Gresham HD, Lindberg FP (2001) CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcgamma and complement receptor-mediated phagocytosis. J Exp Med 193:855–862

    PubMed  CAS  Google Scholar 

  207. Motegi S, Okazawa H, Ohnishi H et al (2003) Role of the CD47-SHPS-1 system in regulation of cell migration. EMBO J 22:2634–2644

    PubMed  CAS  Google Scholar 

  208. Brown EJ, Frazier WA (2001) Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 11:130–135

    PubMed  CAS  Google Scholar 

  209. Borghi N, James Nelson W (2009) Intercellular adhesion in morphogenesis: molecular and biophysical considerations. Curr Top Dev Biol 89:1–32

    PubMed  CAS  Google Scholar 

  210. Krauss RS, Cole F, Gaio U et al (2005) Close encounters: regulation of vertebrate skeletal myogenesis by cell-cell contact. J Cell Sci 118:2355–2362

    PubMed  CAS  Google Scholar 

  211. Rufas O, Fisch B, Ziv S et al (2000) Expression of cadherin adhesion molecules on human gametes. Mol Hum Reprod 6:163–169

    PubMed  CAS  Google Scholar 

  212. Marin-Briggiler CI, Lapyckyj L, Gonzalez Echeverria MF et al (2010) Neural cadherin is expressed in human gametes and participates in sperm-oocyte interaction events. Int J Androl 33:e228–239

    Google Scholar 

  213. Radice GL, Rayburn H, Matsunami H et al (1997) Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 181:64–78

    PubMed  CAS  Google Scholar 

  214. Charlton CA, Mohler WA, Radice GL et al (1997) Fusion competence of myoblasts rendered genetically null for N-cadherin in culture. J Cell Biol 138:331–336

    PubMed  CAS  Google Scholar 

  215. Huttenlocher A, Lakonishok M, Kinder M et al (1998) Integrin and cadherin synergy regulates contact inhibition of migration and motile activity. J Cell Biol 141:515–526

    PubMed  CAS  Google Scholar 

  216. Charrasse S, Comunale F, Fortier M et al (2007) M-cadherin activates Rac1 GTPase through the Rho-GEF trio during myoblast fusion. Mol Biol Cell 18:1734–1743

    PubMed  CAS  Google Scholar 

  217. Mukai A, Kurisaki T, Sato SB et al (2009) Dynamic clustering and dispersion of lipid rafts contribute to fusion competence of myogenic cells. Exp Cell Res 315:3052–3063

    PubMed  CAS  Google Scholar 

  218. Hsiao SP, Chen SL (2010) Myogenic regulatory factors regulate M-cadherin expression by targeting its proximal promoter elements. Biochem J 428:223–233

    PubMed  CAS  Google Scholar 

  219. Zeschnigk M, Kozian D, Kuch C et al (1995) Involvement of M-cadherin in terminal differentiation of skeletal muscle cells. J Cell Sci 108 (Pt 9):2973–2981

    PubMed  CAS  Google Scholar 

  220. Kuch C, Winnekendonk D, Butz S et al (1997) M-cadherin-mediated cell adhesion and complex formation with the catenins in myogenic mouse cells. Exp Cell Res 232:331–338

    PubMed  CAS  Google Scholar 

  221. Hollnagel A, Grund C, Franke WW et al (2002) The cell adhesion molecule M-cadherin is not essential for muscle development and regeneration. Mol Cell Biol 22:4760–4770

    PubMed  CAS  Google Scholar 

  222. Mbalaviele G, Chen H, Boyce BF et al (1995) The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow. J Clin Invest 95:2757–2765

    PubMed  CAS  Google Scholar 

  223. Floridon C, Nielsen O, Holund B et al (2000) Localization of E-cadherin in villous, extravillous and vascular trophoblasts during intrauterine, ectopic and molar pregnancy. Mol Hum Reprod 6:943–950

    PubMed  CAS  Google Scholar 

  224. MacCalman CD, Furth EE, Omigbodun A et al (1996) Regulated expression of cadherin-11 in human epithelial cells: a role for cadherin-11 in trophoblast-endometrium interactions? Dev Dyn 206:201–211

    PubMed  CAS  Google Scholar 

  225. Getsios S, MacCalman CD (2003) Cadherin-11 modulates the terminal differentiation and fusion of human trophoblastic cells in vitro. Dev Biol 257:41–54

    PubMed  CAS  Google Scholar 

  226. Le Naour F, Andre M, Boucheix C et al (2006) Membrane microdomains and proteomics: lessons from tetraspanin microdomains and comparison with lipid rafts. Proteomics 6:6447–6454

    PubMed  Google Scholar 

  227. Ziyyat A, Rubinstein E, Monier-Gavelle F et al (2006) CD9 controls the formation of clusters that contain tetraspanins and the integrin alpha 6 beta 1, which are involved in human and mouse gamete fusion. J Cell Sci 119:416–424

    PubMed  CAS  Google Scholar 

  228. Kaji K, Oda S, Shikano T et al (2000) The gamete fusion process is defective in eggs of Cd9-deficient mice. Nat Genet 24:279–282

    PubMed  CAS  Google Scholar 

  229. Le Naour F, Rubinstein E, Jasmin C et al (2000) Severely reduced female fertility in CD9-deficient mice. Science 287:319–321

    PubMed  Google Scholar 

  230. Miyado K, Yamada G, Yamada S et al (2000) Requirement of CD9 on the egg plasma membrane for fertilization. Science 287:321–324

    PubMed  CAS  Google Scholar 

  231. Rubinstein E, Ziyyat A, Prenant M et al (2006) Reduced fertility of female mice lacking CD81. Dev Biol 290:351–358

    PubMed  CAS  Google Scholar 

  232. Kaji K, Oda S, Miyazaki S et al (2002) Infertility of CD9-deficient mouse eggs is reversed by mouse CD9, human CD9, or mouse CD81; polyadenylated mRNA injection developed for molecular analysis of sperm-egg fusion. Dev Biol 247:327–334

    PubMed  CAS  Google Scholar 

  233. Zhu GZ, Miller BJ, Boucheix C et al (2002) Residues SFQ (173-175) in the large extracellular loop of CD9 are required for gamete fusion. Development 129:1995–2002

    PubMed  CAS  Google Scholar 

  234. Runge KE, Evans JE, He ZY et al (2007) Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution. Dev Biol 304:317–325

    PubMed  CAS  Google Scholar 

  235. Takeda Y, Tachibana I, Miyado K et al (2003) Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes. J Cell Biol 161:945–956

    PubMed  CAS  Google Scholar 

  236. Parthasarathy V, Martin F, Higginbottom A et al (2009) Distinct roles for tetraspanins CD9, CD63 and CD81 in the formation of multinucleated giant cells. Immunology 127:237–248

    PubMed  CAS  Google Scholar 

  237. Ishii M, Iwai K, Koike M et al (2006) RANKL-induced expression of tetraspanin CD9 in lipid raft membrane microdomain is essential for cell fusion during osteoclastogenesis. J Bone Miner Res 21:965–976

    PubMed  CAS  Google Scholar 

  238. Tachibana I, Hemler ME (1999) Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J Cell Biol 146:893–904

    PubMed  CAS  Google Scholar 

  239. Brzoska E, Bello V, Darribere T et al (2006) Integrin alpha3 subunit participates in myoblast adhesion and fusion in vitro. Differentiation 74:105–118

    PubMed  CAS  Google Scholar 

  240. Puissegur MP, Lay G, Gilleron M et al (2007) Mycobacterial lipomannan induces granuloma macrophage fusion via a TLR2-dependent, ADAM9- and beta1 integrin-mediated pathway. J Immunol 178:3161–3169

    PubMed  CAS  Google Scholar 

  241. McNally AK, Anderson JM (2002) Beta1 and beta2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am J Pathol 160:621–630

    PubMed  CAS  Google Scholar 

  242. Coonrod SA, Naaby-Hansen S, Shetty J et al (1999) Treatment of mouse oocytes with PI-PLC releases 70-kDa (pI 5) and 35- to 45-kDa (pI 5.5) protein clusters from the egg surface and inhibits sperm-oolemma binding and fusion. Dev Biol 207:334–349

    PubMed  CAS  Google Scholar 

  243. Alfieri JA, Martin AD, Takeda J et al (2003) Infertility in female mice with an oocyte-specific knockout of GPI-anchored proteins. J Cell Sci 116:2149–2155

    PubMed  CAS  Google Scholar 

  244. Tousseyn T, Jorissen E, Reiss K et al (2006) (Make) stick and cut loose–disintegrin metalloproteases in development and disease. Birth Defects Res C Embryo Today 78:24–46

    PubMed  CAS  Google Scholar 

  245. Kurisaki T, Masuda A, Sudo K et al (2003) Phenotypic analysis of Meltrin alpha (ADAM12)-deficient mice: involvement of Meltrin alpha in adipogenesis and myogenesis. Mol Cell Biol 23:55–61

    PubMed  CAS  Google Scholar 

  246. Kukita T, Wada N, Kukita A et al (2004) RANKL-induced DC-STAMP is essential for osteoclastogenesis. J Exp Med 200:941–946

    PubMed  CAS  Google Scholar 

  247. Mensah KA, Ritchlin CT, Schwarz EM (2010) RANKL induces heterogeneous DC-STAMP(lo) and DC-STAMP(hi) osteoclast precursors of which the DC-STAMP(lo) precursors are the master fusogens. J Cell Physiol 223:76–83

    PubMed  CAS  Google Scholar 

  248. Hotokezaka H, Sakai E, Ohara N et al (2007) Molecular analysis of RANKL-independent cell fusion of osteoclast-like cells induced by TNF-alpha, lipopolysaccharide, or peptidoglycan. J Cell Biochem 101:122–134

    PubMed  CAS  Google Scholar 

  249. Yang M, Birnbaum MJ, MacKay CA et al (2008) Osteoclast stimulatory transmembrane protein (OC-STAMP), a novel protein induced by RANKL that promotes osteoclast differentiation. J Cell Physiol 215:497–505

    PubMed  CAS  Google Scholar 

  250. Sapir A, Avinoam O, Podbilewicz B et al (2008) Viral and developmental cell fusion mechanisms: conservation and divergence. Dev Cell 14:11–21

    PubMed  CAS  Google Scholar 

  251. Oren-Suissa M, Podbilewicz B (2007) Cell fusion during development. Trends Cell Biol 17:537–546

    PubMed  CAS  Google Scholar 

  252. Chernomordik LV, Zimmerberg J, Kozlov MM (2006) Membranes of the world unite! J Cell Biol 175:201–207

    PubMed  CAS  Google Scholar 

  253. Jahn R, Lang T, Sudhof TC (2003) Membrane fusion. Cell 112:519–533

    PubMed  CAS  Google Scholar 

  254. Costa M, Raich W, Agbunag C et al (1998) A putative catenin-cadherin system mediates morphogenesis of the Caenorhabditis elegans embryo. J Cell Biol 141:297–308

    PubMed  CAS  Google Scholar 

  255. Ding M, Woo WM, Chisholm AD (2004) The cytoskeleton and epidermal morphogenesis in C. elegans. Exp Cell Res 301:84–90

    PubMed  CAS  Google Scholar 

  256. McKeown C, Praitis V, Austin J (1998) sma-1 encodes a betaH-spectrin homolog required for Caenorhabditis elegans morphogenesis. Development 125:2087–2098

    PubMed  CAS  Google Scholar 

  257. Duan R, Gallagher PJ (2009) Dependence of myoblast fusion on a cortical actin wall and nonmuscle myosin IIA. Dev Biol 325:374–385

    PubMed  CAS  Google Scholar 

  258. Swailes NT, Colegrave M, Knight PJ et al (2006) Non-muscle myosins 2A and 2B drive changes in cell morphology that occur as myoblasts align and fuse. J Cell Sci 119:3561–3570

    PubMed  CAS  Google Scholar 

  259. Chen A, Leikina E, Melikov K et al (2008) Fusion-pore expansion during syncytium formation is restricted by an actin network. J Cell Sci 121:3619–3628

    PubMed  CAS  Google Scholar 

  260. Richard JP, Leikina E, Chernomordik LV (2009) Cytoskeleton reorganization in influenza hemagglutinin-initiated syncytium formation. Biochim Biophys Acta 1788:450–457

    PubMed  CAS  Google Scholar 

  261. Wurth MA, Schowalter RM, Smith EC et al (2010) The actin cytoskeleton inhibits pore expansion during PIV5 fusion protein-promoted cell-cell fusion. Virology 404:117–126

    PubMed  CAS  Google Scholar 

  262. Berger S, Schafer G, Kesper DA et al (2008) WASP and SCAR have distinct roles in activating the Arp2/3 complex during myoblast fusion. J Cell Sci 121:1303–1313

    PubMed  CAS  Google Scholar 

  263. Gildor B, Massarwa R, Shilo BZ et al (2009) The SCAR and WASp nucleation-promoting factors act sequentially to mediate Drosophila myoblast fusion. EMBO Rep 10:1043–1050

    PubMed  CAS  Google Scholar 

  264. Massarwa R, Carmon S, Shilo BZ et al (2007) WIP/WASp-based actin-polymerization machinery is essential for myoblast fusion in Drosophila. Dev Cell 12:557–569

    PubMed  CAS  Google Scholar 

  265. Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–465

    PubMed  CAS  Google Scholar 

  266. Saarikangas J, Zhao H, Lappalainen P (2010) Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. Physiol Rev 90:259–289

    PubMed  CAS  Google Scholar 

  267. Harmon B, Campbell N, Ratner L (2010) Role of Abl kinase and the Wave2 signaling complex in HIV-1 entry at a post-hemifusion step. PLoS Pathog 6:e1000956

    PubMed  Google Scholar 

  268. Laurin M, Fradet N, Blangy A et al (2008) The atypical Rac activator Dock180 (Dock1) regulates myoblast fusion in vivo. Proc Natl Acad Sci USA 105:15446–15451

    PubMed  CAS  Google Scholar 

  269. Pajcini KV, Pomerantz JH, Alkan O et al (2008) Myoblasts and macrophages share molecular components that contribute to cell-cell fusion. J Cell Biol 180:1005–1019

    PubMed  CAS  Google Scholar 

  270. O‘Brien SP, Seipel K, Medley QG et al (2000) Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proc Natl Acad Sci USA 97:12074–12078

    PubMed  Google Scholar 

  271. Chen EH, Pryce BA, Tzeng JA et al (2003) Control of myoblast fusion by a guanine nucleotide exchange factor, loner, and its effector ARF6. Cell 114:751–762

    PubMed  CAS  Google Scholar 

  272. Dunphy JL, Moravec R, Ly K et al (2006) The Arf6 GEF GEP100/BRAG2 regulates cell adhesion by controlling endocytosis of beta1 integrins. Curr Biol 16:315–320

    PubMed  CAS  Google Scholar 

  273. Faix J, Breitsprecher D, Stradal TE et al (2009) Filopodia: Complex models for simple rods. Int J Biochem Cell Biol 41:1656–1664

    PubMed  CAS  Google Scholar 

  274. Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327:46–50

    PubMed  CAS  Google Scholar 

  275. Prives J, Shinitzky M (1977) Increased membrane fluidity precedes fusion of muscle cells. Nature 268:761–763

    PubMed  CAS  Google Scholar 

  276. Sekiya T, Takenawa T, Nozawa Y (1984) Reorganization of membrane cholesterol during membrane fusion in myogenesis in vitro: a study using the filipin-cholesterol complex. Cell Struct Funct 9:143–155

    PubMed  CAS  Google Scholar 

  277. Waheed AA, Freed EO (2009) Lipids and membrane microdomains in HIV-1 replication. Virus Res 143:162–176

    PubMed  CAS  Google Scholar 

  278. Kielian M, Rey FA (2006) Virus membrane-fusion proteins: more than one way to make a hairpin. Nat Rev Microbiol 4:67–76

    PubMed  CAS  Google Scholar 

  279. Pontow SE, Heyden NV, Wei S et al (2004) Actin cytoskeletal reorganizations and coreceptor-mediated activation of rac during human immunodeficiency virus-induced cell fusion. J Virol 78:7138–7147

    PubMed  CAS  Google Scholar 

  280. Mohler WA, Shemer G, del Campo JJ et al (2002) The type I membrane protein EFF-1 is essential for developmental cell fusion. Dev Cell 2:355–362

    PubMed  CAS  Google Scholar 

  281. Sapir A, Choi J, Leikina E et al (2007) AFF-1, a FOS-1-regulated fusogen, mediates fusion of the anchor cell in C. elegans. Dev Cell 12:683–698

    CAS  Google Scholar 

  282. Mi S, Lee X, Li X et al (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789

    PubMed  CAS  Google Scholar 

  283. Blaise S, de Parseval N, Benit L et al (2003) Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc Natl Acad Sci USA 100:13013–13018

    PubMed  CAS  Google Scholar 

  284. Frendo JL, Olivier D, Cheynet V et al (2003) Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol 23:3566–3574

    PubMed  CAS  Google Scholar 

  285. Blond JL, Lavillette D, Cheynet V et al (2000) An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 74:3321–3329

    PubMed  CAS  Google Scholar 

  286. Marin M, Lavillette D, Kelly SM et al (2003) N-linked glycosylation and sequence changes in a critical negative control region of the ASCT1 and ASCT2 neutral amino acid transporters determine their retroviral receptor functions. J Virol 77:2936–2945

    PubMed  CAS  Google Scholar 

  287. Sun QY (2003) Cellular and molecular mechanisms leading to cortical reaction and polyspermy block in mammalian eggs. Microsc Res Tech 61:342–348

    PubMed  CAS  Google Scholar 

  288. Castellucci M, Kaufmann P, Bischof P (1990) Extracellular matrix influences hormone and protein production by human chorionic villi. Cell Tissue Res 262:135–142

    PubMed  CAS  Google Scholar 

  289. Demonbreun AR, Posey AD, Heretis K et al (2010) Myoferlin is required for insulin-like growth factor response and muscle growth. FASEB J 24:1284–1295

    PubMed  CAS  Google Scholar 

  290. Doherty KR, Demonbreun AR, Wallace GQ et al (2008) The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J Biol Chem 283:20252–20260

    PubMed  CAS  Google Scholar 

  291. Doherty KR, Cave A, Davis DB et al (2005) Normal myoblast fusion requires myoferlin. Development 132:5565–5575

    PubMed  CAS  Google Scholar 

  292. Demonbreun AR, Lapidos KA, Heretis K et al (2010) Myoferlin regulation by NFAT in muscle injury, regeneration and repair. J Cell Sci 123:2413–2422

    PubMed  CAS  Google Scholar 

  293. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    PubMed  CAS  Google Scholar 

  294. Sakuragi N, Matsuo H, Coukos G et al (1994) Differentiation-dependent expression of the BCL-2 proto-oncogene in the human trophoblast lineage. J Soc Gynecol Investig 1:164–172

    PubMed  CAS  Google Scholar 

  295. Chang DW, Xing Z, Pan Y et al (2002) c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J 21:3704–3714

    PubMed  CAS  Google Scholar 

  296. Ka H, Hunt JS (2006) FLICE-inhibitory protein: expression in early and late gestation human placentas. Placenta 27:626–634

    PubMed  CAS  Google Scholar 

  297. Ogle BM, Butters KB, Plummer TB et al (2004) Spontaneous fusion of cells between species yields transdifferentiation and retroviral in vivo. FASEB J 18:548–550

    PubMed  CAS  Google Scholar 

  298. Ferrari G, Cusella-De Angelis G, Coletta M et al (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530

    PubMed  CAS  Google Scholar 

  299. Wang X, Willenbring H, Akkari Y et al (2003) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422:897–900

    PubMed  CAS  Google Scholar 

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Zhou, X., Platt, J.L. (2011). Molecular and Cellular Mechanisms of Mammalian Cell Fusion. In: Dittmar, T., Zänker, K.S. (eds) Cell Fusion in Health and Disease. Advances in Experimental Medicine and Biology, vol 713. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0763-4_4

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