Financial support for the printing of the thesis was kindly provided by:

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2 The studies described in this thesis were performed at the: Department of Cell Biology, Section Membrane Cell Biology, University Medical Center Groningen, The Netherlands and Departments of Oncology and Clinical Neurosciences, University of Calgary, Canada within the Groningen University Graduate School of Behavioral and Cognitive Neurosciences (BCN). This thesis is available in the Library of the University of Groningen. This work was supported by grants from the Dutch Foundation for the Support of MS Research Stichting MS Research, Netherlands Organization of Scientific Research (NWO), and the Foundation De Drie Lichten in The Netherlands. Financial support for the printing of the thesis was kindly provided by: Graduate School of Behavioral and Cognitive Neurosciences (BCN) Rijksuniversiteit Groningen University Medical Center Groningen Leica Microsystems BV. Dutch Foundation for the Support of MS Research Stichting MS Research 2006 by Z. Šišková All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means without written permission of the author and the publisher holding the copyright of the published articles. Cover and layout by Z. Šišková. Printed by: WÖHRMANN PRINT SERVICE, Zutphen, The Netherlands ISBN number:

3 RIJKSUNIVERSITEIT GRONINGEN Extracellular matrix and (re)myelination Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 29 november 2006 om uur door Zuzana Šišková geboren op 4 april 1979 te Piešany, Slowakije

4 Promotor: Co-promotores: Prof. Dr. D. Hoekstra Dr. W. Baron Dr. H. de Vries Beoordelingscommissie: Prof. Dr. H.W.G.M. Boddeke Prof. Dr. J.H.A. de Keyser Prof. Dr. P.G.M. Luiten

5 Paranimfen: Joanna Krzeslak Bert Klunder

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7 Total security is mostly a superstition. It does not exist in nature, nor do the children of men as a whole experience it. Avoiding danger is no safer in the long run then outright exposure. Life is either daring adventure or nothing! Helen Keller Venované pamiatke mojej babiky, silnej, inšpirujúcej ženy; rovnako ako aj daším mojim predkom, ktorí si tvrdou prácou zarábali na svoje živobytie. Pamätám ako si vravievala: Strach má veké oi. Ani ja sa už nikdy nechcem bá

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9 Contents Chapter 1 Introduction and scope of the thesis Exploiting oligodendrocyte biology to target myelin repair: what does it take to (re)myelinate? 11 Chapter 2 Fibronectin interferes with oligodendrocyte (re)myelination by precluding laminin directed signals 43 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Fibronectin impedes myelin sheet-directed flow in oligodendrocytes: a role for a beta 1 integrin-mediated PKC signaling pathway in vesicular trafficking Fibronectin perturbs process outgrowth in oligodendrocytes by misregulating MMP-9 activity A role for gangliosides in morphological oligodendrocyte differentiation and myelin membrane integrity Summary and perspectives Nederlandse samenvatting Acknowledgements

10 Abbreviations BBB blood-brain-barrier bfgf basic fibroblast growth factor BIM bisindolylmaleimide BSA bovine serum albumine CGT galactosyltransferase CNP 2, 3 -cyclic nucleotide 3 -phosphorylase CNS central nervous system DMEM Dulbecco s modified Eagle s medium ECM extracellular matrix EAE experimental autoimmune encephalomyelitis ER endoplasmatic reticulum FCS fetal calf serum FITC fluorescin isothiocyanate Fn fibronectin GalCer galactosyl ceramide GlcCer glucosyl ceramide HEPES N-(2-hydroxyethyl)piperazine-N -2-ethanesulfonic acid IGF insulin-like growth factor kda kilo Dalton LacCer lactosyl ceramide LFB lufol fast blue Ln2 laminin-2 mab monoclonal antibody MAG myelin-associated glycoprotein MAL myelin and lymphocyte protein MARCKS myristoylated alanine-rich C-kinase substrate MBP myelin basic protein MMP matrix metalloproteinase MOG myelin-oligodendrocyte glycoprotein MOSP myelin/oligodendrocyte specific protein MS multiple sclerosis NAWM normal appearing white matter NBDNJ N-butyldeoxynojirijmycin NCAM neural cell adhesion molecule NRG neuregulin NT3 neurotrophin-3 OLG oligodendrocyte OPC oligodendrocyte precursor cell OSP oligodendrocyte specific protein O2A oligodendrocyte-type-2-astrocyte PAGE polyacrylamide gel electrophoresis PBS phosphate-buffered saline PDGF platelet-derived growth factor PDGFR platelet-derived growth factor receptor PFA paraformaldehyde PKC protein kinase C PLL poly-l-lysine PLP proteolipid protein PMA phorbol 12-myristate 13-acetate PNS peripheral nervous system PPPP DL-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol-HCL R-mAb Ranscht monoclonal antibody SDS sodium dodecyl sulphate TEM transmission electron microscopy TGN trans-golgi network Tris tris(hydroxymethyl)aminomethane TRITC tetramethylrhodamine isothiocyabate TX-100 Triton X-100 VSV G vesicular stomatitis virus glycoprotein