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Netrin and Netrin Receptor Expression in the Adult Rat Spinal Cord: Evidence That Myelin-Associated Netrin-L Is an Inhibitor of Neurite Extension

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Netrin and Netrin Receptor Expression in the Adult Rat Spinal Cord: Evidence That Myelin-Associated Netrin-L Is an Inhibitor of Neurite Extension Netrin and netrin receptor expression in the adult rat spinal cord: Evidence that myelin-associated netrin-l is an inhibitor of neurite extension Colleen Manitt Department ofNeurology and Neurosurgery Montreal Neurological Institute, McGill University Montreal, Quebec, Canada September 14, 2004 A thesis submitted to McGill University in partial fulfillment of the requirements for the degree of Doctor ofPhilosophy © Colleen Manitt, 2004 Library and Bibliothèque et 1+1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A ON4 Ottawa ON K1A ON4 Canada Canada Your file Votre référence ISBN: 0-494-12900-X Our file Notre référence ISBN: 0-494-12900-X NOTICE: AVIS: The author has granted a non­ L'auteur a accordé une licence non exclusive exclusive license allowing Library permettant à la Bibliothèque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans loan, distribute and sell th es es le monde, à des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, électronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriété du droit d'auteur ownership and moral rights in et des droits moraux qui protège cette thèse. this thesis. Neither the thesis Ni la thèse ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent être imprimés ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. ln compliance with the Canadian Conformément à la loi canadienne Privacy Act some supporting sur la protection de la vie privée, forms may have been removed quelques formulaires secondaires from this thesis. ont été enlevés de cette thèse. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. ••• Canada TABLE OF CONTENTS Acknowledgements .......................................................................................................... 4 Abstract ............................................................................................................................ 6 Résumé ............................................................................................................................. 8 List of figures ................................................................................................................... 10 List of abbreviations ........................................................................................................ II Contribution of authors .................................................................................................... 13 CHAPTER 1: LITERATURE REVIEW ..................................................................... 15 1. The netrins are guidance cues in the embryonic CNS ......................................... 15 A. The netrin gene family ............................................................................. 16 II. Netrin receptors .................................................................................................... 18 A. The DCC Family of Netrin Receptors ..................................................... 18 B. The UNC-5 homologue family ofnetrin receptors .................................. 19 C. Interaction of netrin family members with identified netrin receptors .... 20 III. Functional interactions between DCC and UNC-5 homologue netrin receptors. 22 IV. Netrin signal transduction and growth cone guidance ......................................... 23 V. Mechanisms that regulate netrin function ............................................................ 26 A. Regulation by cyc\ic nuc\eotides ............................................................. 26 i. Is the Adenosine A2B Receptor a Netrin-I Receptor? ................ 27 B. Receptor targeting to the ceH surface ....................................................... 28 C. Local protein synthesis in growth con es .................................................. 28 D. Protease-mediated c\eavage from plasma membrane .............................. 29 E. DCC receptor silencing: hierarchical control ofaxon guidance function 29 VI. Short-range functions of netrin ............................................................................ 30 A. CNS and PNS ........................................................................................... 30 B. Non-neural tissues .................................................................................... 30 VII. Summary .............................................................................................................. 31 RESEARCH RATIONALE AND OBJECTIVES ...................................................... 32 Preface to chapter 2 .......................................................................................................... 34 CHAPTER 2: WIDESPREAD EXPRESSION OF NETRIN-l BY NEURONS AND OLIGODENDROCYTES IN THE ADULT MAMMALIAN SPINAL CORD ....... 35 1. Summary .............................................................................................................. 36 II. Introduction .......................................................................................................... 37 III. Experimental procedures ..................................................................................... 39 IV. Results .................................................................................................................. 45 V. Discussion ............................................................................................................ 52 Preface to chapter 3 .......................................................................................................... 72 CHAPTER 3: A DEVELOPMENTAL SHIFT IN EXPRESSION OF NETRIN RECEPTORS IN THE RAT SPINAL CORD: PREDOMINANCE OF UNC-5 HOMOLOGUES IN ADULTHOOD ........................................................................... 73 1. Summary .............................................................................................................. 74 II. Introduction .......................................................................................................... 75 2 III. Experimental procedures ...................................................................................... 77 IV. Results .................................................................................................................. 82 V. Discussion ............................................................................................................ 87 Preface to chapter 4 .......................................................................................................... 102 CHAPTER4: EVIDENCE THAT MYELIN-ASSOCIATED NETRIN-l IS AN INHIBITOR OF NEURITE EXTENSION ................................................................. 104 1. Summary .............................................................................................................. 105 II. Introduction .......................................................................................................... 106 III. Experimental procedures ...................................................................................... 108 IV. Results .................................................................................................................. 112 V. Discussion ............................................................................................................ 116 CHAPTER 5: GENERAL DISCUSSION ................................................................... 125 1. Netrin expression in the adult spinal cord ............................................................ 125 II. Does netrin in the spinal cord switch from a long-range to a short-range cue with maturation? .......................................................................................................... 126 III. Netrin and netrin receptor expression in adult neurons ....................................... 128 IV. Changes in netrin and netrin receptor expression in neurons during maturation. 129 V. Potential role of netrin and netrin receptors in neurons ....................................... 130 VI. Netrin-l is expressed by oligodendrocytes and is enriched in periaxonal myelin 131 VII. Netrin-l is a myelin-associated inhibitor of neurite extension ............................ 132 VIII. Intraneuronal cAMP levels determine the response to myelin-associated netrin-l .............................................................................................................................. 133 IX. Myelin regulates netrin receptor levels ................................................................ 135 X. Potential mechanisms that regulate the response to myelin-associated netrin-l . 135 XI. Common signaling pathways ............................................................................... 137 XII. Role ofmyelin-associated netrin following injury .............................................. 138 Conclusions
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