Aberrant development of neuromuscular junctions in glycosylation-defective Largemyd mice |
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| Authors: | Ruth Herbst Thomas Iskratsch Ewald Unger Reginald E. Bittner |
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| Affiliation: | 1. Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria;2. Center of Anatomy and Cell Biology, Neuromuscular Research Department, Medical University of Vienna, A-1090 Vienna, Austria;3. Center for Biomedical Engineering and Physics, Medical University of Vienna, A-1090 Vienna, Austria;1. Institute of Physiology II, University Hospital Bonn, Nussallee 11, 53115 Bonn, Germany;2. Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany;3. Department of Medicine-Cardiology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53127 Bonn, Germany;1. Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK;2. The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK;3. The Jackson Laboratory, Bar Harbor, ME 04609, USA;4. Centre for Integrative Physiology & Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH8 9XD, UK;1. Sorbonne University, INSERM, Institute of Myology, Center of Research in Myology, 75013 Paris, France;2. Department of Physics, Biophysics Group, Friedrich-Alexander-University Erlangen-Nuremberg, D-91052, Erlangen, Germany;1. Department of Dermatology, University Medical Center Freiburg, Freiburg 79104, Germany;2. Department of Pathology, University of Heidelberg, Heidelberg 69120, Germany;3. Department of Paediatric Dermatology, University Children’s Hospital Zurich, Zurich 8091, Switzerland;4. Department of Dermatology, University Hospital Zurich, Zurich 8091, Switzerland;5. Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg 79104, Germany;6. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;7. Comprehensive Cancer Center Freiburg, Freiburg 79106, Germany;8. Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland;9. Folkhälsan Institute of Genetics, University of Helsinki, Helsinki 00014, Finland;10. Department of Dermatology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu 90014, Finland;11. Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00167, Italy;12. Genetic and Rare Diseases Research Area, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00165, Italy |
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| Abstract: | Mice deficient in the glycosyltransferase Large are characterized by severe muscle and central nervous system abnormalities. In this study, we show that the formation and maintenance of neuromuscular junctions in Largemyd mice are greatly compromised. Neuromuscular junctions are not confined to the muscle endplate zone but are widely spread and are frequently accompanied by exuberant nerve sprouting. Nerve terminals are highly fragmented and binding of α-bungarotoxin to postsynaptic acetylcholine receptors (AChRs) is greatly reduced. In vitro, Largemyd myotubes are responsive to agrin but produce aberrant AChR clusters, which are larger in area and less densely packed with AChRs. In addition, AChR expression on the cell surface is diminished suggesting that AChR assembly or transport is defective. These results together with the finding that O-linked glycosylation at neuromuscular junctions of Largemyd mice is compromised indicate that the action of Large is necessary for proper neuromuscular junction development. |
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