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Cell-Cell Fusion: a New Function for Invadosomes

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Cell-Cell Fusion: a New Function for Invadosomes Dispatch R121 understanding of cytokinesis will nematode Caenorhabditis elegans. Genetics proteoglycans in Caenorhabditis elegans: 91, 67–94. embryonic cell division depends on CPG-1 and require that we think ‘outside of the cell’ 7. Xu, X., and Vogel, B.E. (2011). A secreted CPG-2. J. Cell Biol. 173, 985–994. and incorporate a role for the ECM in protein promotes cleavage furrow maturation 14. Xu, X., Rongali, S.C., Miles, J.P., Lee, K.D., and cell division. during cytokinesis. Curr. Biol. 21, 114–119. Lee, M. (2006). pat-4/ILK and unc-112/Mig-2 8. Hubbard, E.J., and Greenstein, D. (2000). The are required for gonad function in Caenorhabditis elegans gonad: a test tube for Caenorhabditis elegans. Exp. Cell Res. 312, cell and developmental biology. Dev. Dyn. 218, 1475–1483. References 2–22. 15. Reverte, C.G., Benware, A., Jones, C.W., and 1. Hynes, R.O. (2009). The extracellular matrix: not 9. Schultz, D.W., Weleber, R.G., Lawrence, G., LaFlamme, S.E. (2006). Perturbing integrin just pretty fibrils. Science 326, 1216–1219. Barral, S., Majewski, J., Acott, T.S., and function inhibits microtubule growth from 2. Pollard, T.D. (2010). Mechanics of cytokinesis Klein, M.L. (2005). HEMICENTIN-1 (FIBULIN-6) centrosomes, spindle assembly, and in eukaryotes. Curr. Opin. Cell Biol. 22, 50–56. and the 1q31 AMD locus in the context of cytokinesis. J. Cell Biol. 174, 491–497. 3. Timpl, R., Sasaki, T., Kostka, G., and Chu, M.L. complex disease: review and perspective. 16. Pellinen, T., Tuomi, S., Arjonen, A., Wolf, M., (2003). Fibulins: a versatile family of Ophthalmic Genet. 26, 101–105. Edgren, H., Meyer, H., Grosse, R., Kitzing, T., extracellular matrix proteins. Nat. Rev. Mol. Cell 10. Dastgheib, K., and Green, W.R. (1994). Rantala, J.K., Kallioniemi, O., et al. (2008). Biol. 4, 479–489. Granulomatous reaction to Bruch’s membrane Integrin trafficking regulated by Rab21 is 4. Dong, C., Muriel, J.M., Ramirez, S., Hutter, H., in age-related macular degeneration. Arch. necessary for cytokinesis. Dev. Cell 15, Hedgecock, E.M., Breydo, L., Baskakov, I.V., Ophthalmol. 112, 813–818. 371–385. and Vogel, B.E. (2006). Hemicentin assembly in 11. Shaw, J.A., Mol, P.C., Bowers, B., the extracellular matrix is mediated by distinct Silverman, S.J., Valdivieso, M.H., Duran, A., 1 structural modules. J. Biol. Chem. 281, and Cabib, E. (1991). The function of chitin Columbia University, Department of 23606–23610. synthases 2 and 3 in the Saccharomyces Pathology and Cell Biology, New York, NY 5. Vogel, B.E., and Hedgecock, E.M. (2001). cerevisiae cell cycle. J. Cell Biol. 114, 10032, USA. 2University of California at San Hemicentin, a conserved extracellular member 111–123. Diego, Cellular and Molecular Medicine, La of the immunoglobulin superfamily, organizes 12. Schmidt, M. (2004). Survival and cytokinesis of epithelial and other cell attachments into Saccharomyces cerevisiae in the absence of Jolla, CA 92093, USA. oriented line-shaped junctions. Development chitin. Microbiology 150, 3253–3260. *E-mail: [email protected] 128, 883–894. 13. Olson, S.K., Bishop, J.R., Yates, J.R., 6. Hodgkin, J., Horvitz, H.R., and Brenner, S. Oegema, K., and Esko, J.D. (2006). (1979). Nondisjunction mutants of the Identification of novel chondroitin DOI: 10.1016/j.cub.2010.12.040 Cell–Cell Fusion: A New Function for Transmission electron microscopy studies showed finger-like FCM cell Invadosomes protrusions apparently invading into the founder cells at the site of cell–cell fusion. Podosomes are cytoskeletal-based structures involved in extracellular matrix Invasive, actin-rich, finger-like remodeling and cellular motility. A new study now implicates podosomes in protrusions have been well pore formation during myoblast fusion. characterized in cells that invade or remodel tissue and are termed Bong Hwan Sung and Alissa Weaver* Previously, it was known that actin invadopodia in cancer cells and filaments accumulate transiently at podosomes in normal cells (or Cell–cell fusion is a highly regulated the site of myoblast fusion [4–6], collectively, invadosomes) [11,12]. event that is critical for many dependent on signaling from However, a role in cell–cell fusion physiological and pathological events, heterotypic adhesion molecules and has not been previously described, including fertilization, muscle downstream regulators of branched and their main function is thought to development, and immune response. actin assembly, including Rac, SCAR be degradation of extracellular matrix During skeletal muscle development, and WASP [7]. Furthermore, both the (ECM), in part due to active trafficking fusion of muscle cells generates SCAR and WASP complex activators of ECM-degrading proteinases to multinucleate and functional muscle of the branched-actin-nucleating sites of protrusion formation (Figure 1). fibers and aberrant fusion has been Arp2/3 complex were known to be The myoblast structures observed implicated in dystrophic muscle essential for myoblast fusion [5,6,8–10]. by Sens et al. [3] seemed to be diseases [1,2]. Recently, a number However, the nature of the fusion a potential variation of podosomes, of groups have studied myoblast fusion structure and the roles of individual as they were morphologically similar during body wall muscle formation in actin regulators were poorly by electron microscopy and even had Drosophila melanogaster as understood. adhesion ring structures, albeit a genetically tractable in vivo model To determine whether the prominent cell–cell rather than cell–ECM system to study cell–cell fusion [1]. actin accumulations at pre-fusion sites adhesions. If these structures really In a new study published in the were unique to a muscle cell subtype, were podosomes, the new data Journal of Cell Biology, Sens et al. [3] Sens et al. [3] expressed GFP–actin revealed that podosomes might be investigated the role of actin assembly under the control of FCM-specific or more versatile than previously in formation of the fusion pore during founder-cell-specific promoters and appreciated and also that they are Drosophila myoblast fusion. costained for all actin filaments in formed in vivo during developmental Interestingly, they find that an invasive, embryos with fluorescent phalloidin. ‘invasions’. actin-rich, podosome-like structure is Interestingly, the large actin foci were To determine whether the FCM used by fusion-competent myoblasts exclusively found in FCM cells and actin-rich protrusions resembled (FCMs) to adhere to and fuse with were associated with a deformation podosomes at the molecular level, muscle founder cells. in the founder cell membrane. Sens et al. [3] manipulated the Current Biology Vol 21 No 3 R122 A Myoblast podosome B ECM-degrading podosome N N Fusion- competent myoblast F WASP F M N-WASP M ? WASP ? Sns F Fusogen-containing Duf vesicles Founder cell M Integrin ring ECM degradation M MMP-containing N Extracellular matrix M M N SCAR M vesicles Current Biology Figure 1. Comparison of myoblast podosome with ECM-degrading podosome. (A) Actin assembly is required on both the fusion-competent myoblast and founder cell membranes for initiation of fusion pore formation. Although WASP and SCAR have redundant functions in the formation of actin foci in FCM podosome structures, WASP is essential for invasion of FCM podosomes into founder cells and SCAR induces the formation of a thin actin layer at the pre-fusion site in founder cells. Similar to traditional podosomes (B), myoblast podosomes have an adhesion ring; however, the molecular components are immunoglobulin (Ig) super- family cell–cell adhesion receptors found in the FCM (Sns ring) and founder cells (Duf ring). Fusogen-containing vesicles may be trafficked to podosomes to promote cell fusion. (B) WASP/N-WASP promotes formation of branched-actin-rich, ECM-degrading podosomes. Rings contain- ing integrins and focal adhesion proteins are formed around ECM-degrading podosomes. Matrix metalloproteinases (MMPs) are embedded in vesicles, transported to podosomes, and secreted to induce ECM degradation. N, nucleus. SCAR and WASP regulators formation of actin-rich, invasive ribosomes and other organelles but of branched-actin assembly and podosomes that protrude into founder not actin. Thus, after fusion pore determined the effects on F-actin cells and allow extensive membrane initiation, rapid disassembly of foci formation and myoblast fusion. contact at the pre-fusion site. actin and pore expansion is likely to Loss of both protein complexes in In founder cells, SCAR promotes occur. scar,sltr double mutants led to loss formation of a thin actin layer at the Overall, the study by Sens et al. [3] of the FCM actin focus, verifying that pre-fusion site and is necessary provides an elegant example of the it is a branched-actin-based structure. for cell fusion. These two actin versatility of actin-based structures However, the actin focus was present structures may allow close enough for cellular invasion processes in vivo. in single scar or sltr mutants, apposition and/or curvature of the Although a previous study had shown suggesting compensation of one membranes for fusion to initiate. that leukocytes use podosomes as branched-actin regulator for the other. They may also serve as docking sites adhesion and invasion structures More interesting, however, was the for vesicles containing fusogenic during transcytosis of endothelial cells finding that, despite continued factors, such as lipid rafts (Figure 1) [16] , podosomes had not been formation of the F-actin foci on the FCM [13,14]. Notably, Golgi-derived previously identified as mediators of side of the pre-fusion site, loss of vesicles with electron-dense rims have direct fusion of two cells. Indeed, WASP but not SCAR complexes led been observed to move toward the dogma in the field has been that to defective formation of invasive muscle-cell contact sites in Drosophila podosomes are structures that protrusions and lack of FCM invasion embryos [5].
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