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Abstract
Heparan sulfate proteoglycans (HSPGs) are critical modulators of growth factor activities. Skeletal muscle differentiation is strongly inhibited by fibroblast growth factor 2 (FGF-2). We have shown that HSPGs present at the plasma membrane are expressed in myoblasts and are downregulated during muscle differentiation. An exception is glypican-1, which is present throughout the myogenic process. Myoblasts that do not express glypican-1 exhibit defective differentiation, with an increase in the receptor binding of FGF-2, concomitant with increased signaling. Glypican-1-deficient myoblasts show decreased expression of myogenin, the master gene that controls myogenesis, myosin, and the myoblast fusion index. Reversion of these defects was induced by expression of rat glypican-1. Glypican-1 is the only HSPG localized in lipid raft domains in myoblasts, resulting in the sequestration of FGF-2 away from FGF-2 receptors (FGFRs) located in nonraft domains. A chimeric glypican-1, containing syndecan-1 transmembrane and cytoplasmic domains, is located in nonraft domains interacting with FGFR-IV- and enhanced FGF-2-dependent signaling. Thus, glypican-1 acts as a positive regulator of muscle differentiation by sequestering FGF-2 in lipid rafts and preventing its binding and dependent signaling.
We are indebted to David J. Carey (Siegfried and Janet Weiss Center for Research, Danville, PA) and to Ralph D. Sanderson (University of Alabama at Birmingham, AL) for providing anti glypican-1 antibody and pcDNA 3.0-rat-glypican-1, respectively. We thank Juan Larraín and Hugo Olguín (P. Universidad Católica de Chile) for offering encouragement and helpful suggestions.
This study was supported by research grants from FONDAP-Biomedicine (grants 13980001 and CARE PFB 12/2007) and the Muscular Dystrophy Association (grant 89419) as well as by the doctoral fellowship granted to Jaime A. Gutierrez by CONYCYT, Chile.