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Published online March 10, 2008
doi:10.1083/jcb.200707191
The Journal of Cell Biology, Vol. 180, No. 5, 1005-1019
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Pajcini et al.
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Article

Myoblasts and macrophages share molecular components that contribute to cell–cell fusion

Kostandin V. Pajcini1, Jason H. Pomerantz2, Ozan Alkan1, Regis Doyonnas1, and Helen M. Blau1

1 Department of Microbiology & Immunology, Baxter Laboratory in Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA 94305
2 Department of Surgery, Division of Plastic and Reconstructive Surgery, University of California, San Francisco, San Francisco, CA 94143

Correspondence to Helen M. Blau: hblau{at}stanford.edu; or Jason H. Pomerantz: jason.pomerantz{at}ucsfmedctr.org

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 β1-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.

K.V. Pajcini and J.H. Pomerantz contributed equally to this paper.

Abbreviations used in this paper: ARF6, ADP ribosylation factor 6; β-gal, β-galactosidase; BM, bone marrow; DKD, double knockdown; DM, differentiation media; GEF, guanine-nucleotide exchange factor; GM, growth media; IL-4, interleukin-4; MHC, myosin heavy chain; MNGC, multinucleated giant cell; shRNA, short hairpin RNA.


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