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The Journal of Neuroscience, July 2, 2003, 23(13):5393-5406
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Nogo-A Inhibits Neurite Outgrowth and Cell Spreading with Three Discrete Regions
Thomas Oertle,1 * Marjan E. van der Haar,1 * Christine E. Bandtlow,2 Anna Robeva,3 Patricia Burfeind,3 Armin Buss,1 Andrea B. Huber,1 Marjo Simonen,1 Lisa Schnell,1 Christian Brösamle,1 Klemens Kaupmann,4 Rüdiger Vallon,3 andMartin E. Schwab1 1Brain Research Institute, University of Zurich, and Department of Biology, Swiss Federal Institute of Technology, CH-8057 Zurich, Switzerland, 2Institute of Medical Chemistry and Biochemistry, Leopold-Franzens-University of Innsbruck, A-6020 Innsbruck, Austria, 3Novartis Institute for Biomedical Research, Functional Genomics, Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901, and 4Novartis Pharma AG, Nervous System Research, CH-4002 Basel, Switzerland
Nogo-A is a potent neurite growth inhibitor in vitro and plays a role both in the restriction of axonal regeneration after injury and in structural plasticity in the CNS of higher vertebrates. The regions that mediate inhibition and the topology of the molecule in the plasma membrane have to be defined. Here we demonstrate the presence of three different active sites: (1) an N-terminal region involved in the inhibition of fibroblast spreading, (2) a stretch encoded by the Nogo-A-specific exon that restricts neurite outgrowth and cell spreading and induces growth cone collapse, and (3) a C-terminal region (Nogo-66) with growth cone collapsing function. We show that Nogo-A-specific active fragments bind to the cell surface of responsive cells and to rat brain cortical membranes, suggesting the existence of specific binding partners or receptors. Several antibodies against different epitopes on the Nogo-A-specific part of the protein as well as antisera against the 66 aa loop in the C-terminus stain the cell surface of living cultured oligodendrocytes. Nogo-A is also labeled by nonmembrane-permeable biotin derivatives applied to living oligodendrocyte cultures. Immunofluorescent staining of intracellular, endoplasmic reticulum-associated Nogo-A in cells after selective permeabilization of the plasma membrane reveals that the epitopes of Nogo-A, shown to be accessible at the cell surface, are exposed to the cytoplasm. This suggests that Nogo-A could have a second membrane topology. The two proposed topological variants may have different intracellular as well as extracellular functions.
Key words: Nogo; reticulon; inhibitory regions; active sites; membrane topology; neurite outgrowth
Received Jul. 30, 2002; revised Apr. 14, 2003; accepted Apr. 15, 2003.
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