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Disruption of perlecan binding and matrix assembly by post-translational or genetic disruption of dystroglycan function

Department of Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, 400 Eckstein Medical Building, Iowa City, IA 52242, USA.
FEBS Letters (Impact Factor: 3.34). 09/2005; 579(21):4792-6. DOI: 10.1016/j.febslet.2005.07.059
Source: PubMed

ABSTRACT Dystroglycan is a cell-surface matrix receptor that requires LARGE-dependent glycosylation for laminin binding. Although the interaction of dystroglycan with laminin has been well characterized, less is known about the role of dystroglycan glycosylation in the binding and assembly of perlecan. We report reduced perlecan-binding activity and mislocalization of perlecan in the LARGE-deficient Large(myd) mouse. Cell-surface ligand clustering assays show that laminin polymerization promotes perlecan assembly. Solid-phase binding assays provide evidence for the first time of a trimolecular complex formation of dystroglycan, laminin and perlecan. These data suggest functional disruption of the trimolecular complex in glycosylation-deficient muscular dystrophy.

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    • "Additionally, alterations to the basal lamina microenvironment may further impinge upon satellite cell activity. Dystroglycan has been shown to organize laminin and other basal lamina components into networks and as such has been attributed with a primary role in basement membrane deposition [6, 35]. Given the well-documented mitogenic effect of laminin on myoblasts [30, 31, 36], any disruption in its ability to bind to laminin might be expected to influence the satellite cell niche. "
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    ABSTRACT: The dystrophin-associated glycoprotein complex (DGC) is found at the muscle fiber sarcolemma and forms an essential structural link between the basal lamina and internal cytoskeleton. In a set of muscular dystrophies known as the dystroglycanopathies, hypoglycosylation of the DGC component α-dystroglycan results in reduced binding to basal lamina components, a loss in structural stability, and repeated cycles of muscle fiber degeneration and regeneration. The satellite cells are the key stem cells responsible for muscle repair and reside between the basal lamina and sarcolemma. In this study, we aimed to determine whether pathological changes associated with the dystroglycanopathies affect satellite cell function. In the Large(myd) mouse dystroglycanopathy model, satellite cells are present in significantly greater numbers but display reduced proliferation on their native muscle fibers in vitro, compared with wild type. However, when removed from their fiber, proliferation in culture is restored to that of wild type. Immunohistochemical analysis of Large(myd) muscle reveals alterations to the basal lamina and interstitium, including marked disorganization of laminin, upregulation of fibronectin and collagens. Proliferation and differentiation of wild-type satellite cells is impaired when cultured on substrates such as collagen and fibronectin, compared with laminins. When engrafted into irradiated tibialis anterior muscles of mdx-nude mice, wild-type satellite cells expanded on laminin contribute significantly more to muscle regeneration than those expanded on fibronectin. These results suggest that defects in α-dystroglycan glycosylation are associated with an alteration in the satellite cell niche, and that regenerative potential in the dystroglycanopathies may be perturbed. STEM Cells2012;30:2330-2341.
    Stem Cells 10/2012; 30(10):2330-41. DOI:10.1002/stem.1197 · 7.70 Impact Factor
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    • "The α-DG is modified by three different types of glycans such as: mucin type O-glycosylation, O-mannosylation, and N-glycosylation. The glycosylated α-DG is essential for the protein's ability to bind the laminin globular domaincontaining proteins of the Extracellular Matrix (Kanagawa, 2005). LARGE is required for the generation of functional, properly glycosylated forms of α-DG (Barresi, 2004). "
    Computational Biology and Applied Bioinformatics, 09/2011; , ISBN: 978-953-307-629-4
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    • "Dystroglycan is encoded by a single gene (DAG1) and is cleaved into two proteins, a-dystroglycan (a-DG) and b-dystroglycan (b-DG), by posttranslational processing (Ibraghimov-Beskrovnaya et al., 1992). DGs are central components of the dystrophin– glycoprotein complex (DGC) at the sarcolemma, and a-DG was shown to serve as a cell surface receptor for laminin (Ibraghimov-Beskrovnaya et al., 1992), agrin (Gee et al., 1994; Campanelli et al., 1994), perlecan (Peng et al., 1998; Kanagawa et al., 2005), and neurexin (Sugita et al., 2001). In skeletal muscle , the laminin-a-DG linkage is thought to be critical for plasma membrane stability (recently reviewed in Kanagawa and Toda 2006). "
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    ABSTRACT: Protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) is an enzyme that transfers N-acetylglucosamine to O-mannose of glycoproteins. Mutations of the POMGnT1 gene cause muscle-eye-brain (MEB) disease. To obtain a better understanding of the pathogenesis of MEB disease, we mutated the POMGnT1 gene in mice using a targeting technique. The mutant muscle showed aberrant glycosylation of alpha-DG, and alpha-DG from mutant muscle failed to bind laminin in a binding assay. POMGnT1(-/-) muscle showed minimal pathological changes with very low-serum creatine kinase levels, and had normally formed muscle basal lamina, but showed reduced muscle mass, reduced numbers of muscle fibers, and impaired muscle regeneration. Importantly, POMGnT1(-/-) satellite cells proliferated slowly, but efficiently differentiated into multinuclear myotubes in vitro. Transfer of a retrovirus vector-mediated POMGnT1 gene into POMGnT1(-/-) myoblasts completely restored the glycosylation of alpha-DG, but proliferation of the cells was not improved. Our results suggest that proper glycosylation of alpha-DG is important for maintenance of the proliferative activity of satellite cells in vivo.
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