title: LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy.
abstract: The dense glycan coat that surrounds every cell is essential for cellular development and physiological function, and it is becoming appreciated that its composition is highly dynamic. Post-translational addition of the polysaccharide repeating unit [-3-xylose-α1,3-glucuronic acid-β1-]n by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein dystroglycan to function as a receptor for proteins in the extracellular matrix. Reductions in the amount of [-3-xylose-α1,3-glucuronic acid-β1-]n (hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous forms of muscular dystrophy. However, neither patient nor mouse studies has revealed a clear correlation between glycosylation status and phenotype. This disparity can be attributed to our lack of knowledge of the cellular function of the LARGE-glycan repeat. Here we show that coordinated upregulation of Large and dystroglycan in differentiating mouse muscle facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized LARGE-glycan repeats we show a direct correlation between LARGE-glycan extension and its binding capacity for extracellular matrix ligands. Blocking Large upregulation during muscle regeneration results in the synthesis of dystroglycan with minimal LARGE-glycan repeats in association with a less compact basement membrane, immature neuromuscular junctions and dysfunctional muscle predisposed to dystrophy. This was consistent with the finding that patients with increased clinical severity of disease have fewer LARGE-glycan repeats. Our results reveal that the LARGE-glycan of dystroglycan serves as a tunable extracellular matrix protein scaffold, the extension of which is required for normal skeletal muscle function.
authors.affiliation: 1] Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA [2] Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Goddeeris
authors.forename: Biming
authors.initials: B
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Venzke
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshida-Moriguchi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Saito
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Matsumura
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D049030:Dystroglycans / Q000737:chemistry* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D024510:Muscle Development; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032446:Myoblasts; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D011134:Polysaccharides; D049030:Dystroglycans; C117674:LARGE1 protein, human; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases