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The Journal of Neuroscience, September 3, 2008, 28(36):8897-8907; doi:10.1523/JNEUROSCI.2171-08.2008

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Development/Plasticity/Repair
Fibroblast Growth Factor-Regulated Palmitoylation of the Neural Cell Adhesion Molecule Determines Neuronal Morphogenesis

Evgeni Ponimaskin,^1 * Galina Dityateva,^2,3 * Mika O. Ruonala,^4,5 Masaki Fukata,^6,7 Yuko Fukata,^6,7 Fritz Kobe,¹ Fred S. Wouters,⁴ Markus Delling,⁸ David S. Bredt,⁹ Melitta Schachner,^2,10,11 and Alexander Dityatev^2,3

¹Abteilung Neuro- und Sinnesphysiologie, Physiologisches Institut, Universität Göttingen, 37073 Göttingen, Germany, ²Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany, ³Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, 16163 Genova, Italy, ⁴European Neuroscience Institute, 37085 Göttingen, Germany, ⁵Center for Membrane Proteomics, University of Frankfurt am Main, 60438 Frankfurt am Main, Germany, ⁶Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki 444-8787, Japan, ⁷PRESTO, Japan Science and Technology Agency, Chiyoda, Tokyo 102-0075, Japan, ⁸Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, ⁹Department of Integrative Biology, Eli Lilly and Company, Indianapolis, Indiana 46285, ¹⁰W.M. Keck Center for Collaborative Neuroscience, and ¹¹Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854

Correspondence should be addressed to either of the following: Alexander Dityatev, Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy, Email: alexander.dityatev{at}iit.it; or Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 85, D-20251 Hamburg, Germany, E-mail: Email: melitta.schachner{at}zmnh.uni-hamburg.de

During development of the nervous system, short- and long-range signals cooperate to promote axonal growth, guidance, and target innervation. Particularly, a short-range signal transducer, the neural cell adhesion molecule (NCAM), stimulates neurite outgrowth via mechanisms that require posttranslational modification of NCAM and signaling via receptors to a long-range messenger, the fibroblast growth factor (FGF). In the present study we further characterized a mechanism which regulates the functional interplay between NCAM and FGF receptor(s). We show that activation of FGF receptor(s) by FGF2 leads to palmitoylation of the two major transmembrane NCAM isoforms, NCAM140 and NCAM180, translocation of NCAM to GM1 ganglioside-containing lipid rafts, and stimulation of neurite outgrowth of hippocampal neurons. Ablation of NCAM, mutation of NCAM140 or NCAM180 palmitoylation sites, or pharmacological suppression of NCAM signaling inhibited FGF2-stimulated neurite outgrowth. Of the 23 members of the aspartate-histidine-histidine-cysteine (DHHC) domain containing proteins, DHHC-7 most strongly stimulated palmitoylation of NCAM, and enzyme activity was enhanced by FGF2. Thus, our study uncovers a molecular mechanism by which a growth factor regulates neuronal morphogenesis via activation of palmitoylation, which in turn modifies subcellular location and thus signaling via an adhesion molecule.

Key words: acylation; palmitoylation; cell adhesion; growth factor; lipid raft; neurite outgrowth; FLIM; FRET; hippocampus

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Received May 13, 2008; revised July 23, 2008; accepted July 29, 2008.

Correspondence should be addressed to either of the following: Alexander Dityatev, Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy, Email: alexander.dityatev{at}iit.it; or Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 85, D-20251 Hamburg, Germany, E-mail: Email: melitta.schachner{at}zmnh.uni-hamburg.de

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