title: Removal of dystroglycan causes severe muscular dystrophy in zebrafish embryos.
abstract: Muscular dystrophy is frequently caused by disruption of the dystrophin-glycoprotein complex (DGC), which links muscle cells to the extracellular matrix. Dystroglycan, a central component of the DGC, serves as a laminin receptor via its extracellular alpha subunit, and interacts with dystrophin (and thus the actin cytoskeleton) through its integral membrane beta subunit. We have removed the function of dystroglycan in zebrafish embryos. In contrast to mouse, where dystroglycan mutations lead to peri-implantation lethality, dystroglycan is dispensable for basement membrane formation during early zebrafish development. At later stages, however, loss of dystroglycan leads to a disruption of the DGC, concurrent with loss of muscle integrity and necrosis. In addition, we find that loss of the DGC leads to loss of sarcomere and sarcoplasmic reticulum organisation. The DGC is required for long-term survival of muscle cells in zebrafish, but is dispensable for muscle formation. Dystroglycan or the DGC is also required for normal sarcomere and sarcoplasmic reticulum organisation. Because zebrafish embryos lacking dystroglycan share several characteristics with human muscular dystrophy, they should serve as a useful model for the disease. In addition, knowing the dystroglycan null phenotype in zebrafish will facilitate the isolation of other molecules involved in muscular dystrophy pathogenesis.
authors.affiliation: Division of Developmental Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parsons
authors.forename: Isabel
authors.initials: I
authors.lastname: Campos
authors.forename: Elizabeth M A
authors.initials: EM
authors.lastname: Hirst
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
mesh_terms: D000818:Animals; D001483:Base Sequence; D002490:Central Nervous System / Q000196:embryology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D049030:Dystroglycans; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006801:Humans; D017403:In Situ Hybridization; D007797:Laminin / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018482:Muscle, Skeletal / Q000196:embryology; D009137:Muscular Dystrophy, Animal / Q000209:etiology* / Q000235:genetics; D009469:Neuromuscular Junction / Q000196:embryology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D007797:Laminin; D008562:Membrane Glycoproteins; D020319:Oligodeoxyribonucleotides, Antisense; C121346:laminin 1; D049030:Dystroglycans