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Peripheral Myelin Protein 22 (Pmp22) Is in a Complex with Alpha6 Beta4 Integrin and the Absence of Pmp22 Affects Schwann Cell Adhesion and Migration

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Peripheral Myelin Protein 22 (Pmp22) Is in a Complex with Alpha6 Beta4 Integrin and the Absence of Pmp22 Affects Schwann Cell Adhesion and Migration PERIPHERAL MYELIN PROTEIN 22 (PMP22) IS IN A COMPLEX WITH ALPHA6 BETA4 INTEGRIN AND THE ABSENCE OF PMP22 AFFECTS SCHWANN CELL ADHESION AND MIGRATION By STEPHANIE ANN AMICI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006 Copyright 2006 by Stephanie Ann Amici I dedicate this work to my family for their constant love and support. ACKNOWLEDGMENTS Most importantly, I would like to thank my advisor, Dr. Lucia Notterpek, for the inspiration and support she has given to me. She has always had my best interests in mind and has been essential in my growth as a scientist and as a person. I also express my gratitude to my committee members, Dr. Brad Fletcher, Dr. Dena Howland, Dr. Harry Nick and Dr. Susan Frost, for their insights and suggestions for my project. Similarly, Dr. William Dunn deserves acknowledgement for his advice and assistance with the electron microscopy studies. Heartfelt thanks also go to the past and present members of the Notterpek lab for their amazing friendships over the years. Finally, my deepest gratitude goes to my family, especially my parents, for their continuous love and encouragement throughout my life. iv TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF FIGURES .......................................................................................................... vii LIST OF ABBREVIATIONS............................................................................................ ix ABSTRACT....................................................................................................................... xi CHAPTER 1 INTRODUCTION ........................................................................................................1 Constituents of Myelin .................................................................................................3 Peripheral Myelin Protein 22-Associated Hereditary Peripheral Neuropathies...........5 Animal Models of PMP22-Associated Peripheral Neuropathies .................................8 Potential Disease Mechanisms of PMP22 Neuropathies............................................10 Potential Roles of PMP22 in Cell Biology.................................................................11 2 PERIPHERAL MYELIN PROTEIN 22 IS IN COMPLEX WITH ALPHA6 BETA4 INTEGRIN AND ITS ABSENCE ALTERS THE SCHWANN CELL BASAL LAMINA ......................................................................................................18 Note.............................................................................................................................18 Introduction.................................................................................................................18 Materials and Methods ...............................................................................................20 PMP22-deficient LacZ Mice ...............................................................................20 Morphological Analyses and Teased Nerve Fiber Preparation...........................20 Myelinating Dorsal Root Ganglion (DRG) Neuron-SC Cocultures....................22 Immunolabeling of Nerves..................................................................................22 Western Blot Analyses ........................................................................................23 Coimmunoprecipitation of Integrins and PMP22................................................24 Cell Surface Labeling..........................................................................................25 Protein Interaction Studies in Clone A Cells.......................................................25 Results.........................................................................................................................26 Phenotype of PMP22-deficient LacZ Mice.........................................................26 Delayed Myelination and Altered SC-ECM Interactions in the Absence of PMP22..............................................................................................................31 β4 Integrin Levels Are Reduced in Sciatic Nerves of PMP22 -/- Mice..............34 v PMP22 Is in a Complex with α6β4 Integrin and Laminin..................................36 Discussion...................................................................................................................42 3 DELAYED MYELINATION AND ALTERED NODAL ORGANIZATION IN PERIPHERAL MYELIN PROTEIN 22-DEFICIENT MICE....................................48 Introduction.................................................................................................................48 Materials and Methods ...............................................................................................51 Myelinating DRG Explant Cultures ....................................................................51 Teased Nerve Fiber Preparation ..........................................................................51 Immunolabeling of Nerves and Myelinating DRG Explant Cultures .................52 Western Blot Analyses ........................................................................................53 Statistics...............................................................................................................54 Results.........................................................................................................................54 Altered Myelin Protein Expression and Localization in PMP22 -/- Mice ..........54 Changes in Integrin Expression Patterns in the Absence of PMP22...................58 Myelination Is Impaired in DRG Explant Cultures from PMP22 -/- Mice.........61 Discussion...................................................................................................................64 4 THE ADHESION AND MIGRATION OF SCHWANN CELLS IS ALTERED IN THE ABSENCE OF PERIPHERAL MYELIN PROTEIN 22 .............................68 Introduction.................................................................................................................68 Materials and Methods ...............................................................................................70 Mouse Schwann Cell Isolation............................................................................70 LacZ Activity Assay............................................................................................71 Bromodeoxyuridine Incorporation Assay ...........................................................71 Immunocytochemistry.........................................................................................71 Western Analyses ................................................................................................72 Adhesion Assays .................................................................................................72 Migration Assays.................................................................................................73 Results.........................................................................................................................74 PMP22 Is Expressed in Nonmyelinating SCs .....................................................74 Increased SC Proliferation in the Absence of PMP22.........................................76 PMP22-Deficient Cells Display Impaired Adhesion and Migration...................77 Lack of PMP22 Results in Altered SC Morphology ...........................................79 Discussion...................................................................................................................82 5 CONCLUSIONS ........................................................................................................86 Overview of Findings .................................................................................................86 Unresolved Issues and Future Studies ........................................................................89 LIST OF REFERENCES...................................................................................................93 BIOGRAPHICAL SKETCH ...........................................................................................108 vi LIST OF FIGURES Figure page 1-1 The myelination program ...........................................................................................2 1-2 Putative PMP22 structure...........................................................................................5 2-1 Schematic representation of the targeting strategy ..................................................27 2-2 Widespread β-gal expression in the E15 mouse embryo .........................................28 2-3 Phenotype of adult PMP22-deficient mice...............................................................30 2-4 Delayed myelination and ultrastructural alterations in nerves of affected mice ......33 2-5 Decreased levels of β4 integrin in nerves of PMP22-deficient mice.......................35 2-6 PMP22 is in a complex with α6β4 integrin and laminin .........................................37 2-7 Coexpression of PMP22 and integrins during myelination .....................................39 2-8 PMP22 and β4 integrin are coimmunoprecipitated from clone A cells...................41 3-1 The expression of myelin proteins is delayed in nerves from PMP22-deficient mice ..........................................................................................................................55
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