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Phd-Thesis Gernot Walko Final Version DISSERTATION Titel der Dissertation Functions of plectin and its isoforms assessed in mouse stratified epithelia and keratinocyte cell cultures angestrebter akademischer Grad Doktor der Naturwissenschaften (Dr. rer.nat.) Verfasserin / Verfasser: Mag. Gernot Walko Matrikel-Nummer: 9607581 Dissertationsgebiet Molekulare Biologie (lt. Studienblatt): Betreuerin / Betreuer: Univ.-Prof. Dr. Gerhard Wiche Wien, am 10.12.2007 In der Wissenschaft gleichen wir alle nur den Kindern, die am Rande des Wissens hie und da einen Kiesel aufheben, während sich der weite Ozean des Unbekannten vor unseren Augen erstreckt. Isaac Newton (1643-1727), engl. Physiker, Mathematiker u. Astronom DANKSAGUNG I DANKSAGUNG Auf fast 200 Seiten – prallvoll mit Wissen und Wissenschaft – sollte man die Einflüsse vieler kluger Leute erwarten, und so ist es auch. Im Einzelnen danke ich: Prof. Dr. Gerhard Wiche für ein spannendes Dissertationsgebiet, viele interessante Diskussionen und viel Freiheit beim Forschen. Dr. Kerstin Andrä-Marobela für das Lehren von Allem was für die Wissenschaft von Bedeutung ist, inklusive dem Durchsetzen des eigenen Sturkopfes. Prof. Dr. Roland Foisner und Prof. Dr. Milos Pekny für das Lesen und Beurteilen einer sehr dicken Dissertation. Prof. Dr. Fritz Propst und Dr. Christina Abrahamsberg für ihr Mentoring, inklusive Schulterklopfen, Aufmuntern und vieler langer Gespräche bei vielen Tassen Kaffee. Prof. Dr. Fritz Pittner für so manch aufmunterndes Wort. Prof. Dr. Matthias Schmuth für das weltumspannende Verschicken kostbarer Messgeräte und das Beisteuern guter Ideen. Prof. Dr. Thomas Marlovits und Dr. Philip Zeller für die Benützung einer wunderbaren Maschine zum Auseinanderdehnen von Zellen. Prof. Dr. Milos Pekny für aufmunternde Worte wann und wo wir uns auch immer begegnet sind. Dr. Peter Fuchs für das Lehren vom richtigen Umgang mit kleinen (bissigen) Nagetieren. Irmgard Fischer für die Herstellung unzähliger großartiger Mikroskoppräparate. DANKSAGUNG II Elisabeth Jursa für prompte Hilfestellungen in Zellkulturfragen. Dr. Lubomir Janda and Mag. Julius Kostan für ihr Fachwissen rund ums Exprimieren und Aufreinigen von Proteinen. Dr. Reinhard Ackerl, Dr. Selma Osmanagic-Myers, Dr. Martin Gregor und Dr. Gerald Burgstaller für das Teilen von Freud und Leid beim Publizieren. Dr. Reinhard Ackerl, Dr. Selma Osmanagic-Myers, Mag. Nevena Vukasinovic, Dr. Günter Rezniczek, Dr. Siegfried Reipert und Dr. Anikó Zeold für eine wahnsinning tolle Zeit im Labor 2. Gerlinde Aschauer für das Verkörpern des „Guten Geistes“ unseres Institutes und für ihr großes Verständnis studentischer Probleme. Meinen Freunden Wolfi, Steffi, Christine, Sandra, Thomas und Alex für ihre wunderbare Freundschaft. Meinen drei Familien im Süden und Westen dieses Landes für alles wofür man Familie hat und braucht. Meinen Eltern für ihre bedingungslose Unterstützung des armen Studenten, viel Verständnis und für das frühe Erwecken von wissenschaftlichem Interesse. Im großen Kreislauf der Natur ist Ende gleich Anfang. Dieser schönen Logik zufolge beginnt eine Danksagung eigentlich erst so richtig mit dem Ende. So, wie auch alle meine Tage beginnen und enden mit dem Schönsten, das man sich wünschen kann, nämlich der großen Liebe. Dir, mein Schatz, danke ich einfach für Alles! DANKSAGUNG III TABLE OF CONTENTS IV TABLE OF CONTENTS Danksagung ............................................................................................................................. i Table of contents ................................................................................................................... iv Table of figures ...................................................................................................................... ix Abbreviations ........................................................................................................................ xii Summary ..................................................................................................................................1 Zusammenfassung ..................................................................................................................3 Introduction ...............................................................................................................................5 The cytoskeleton .................................................................................................................5 Actin (micro) filaments ...................................................................................................5 Microtubules ....................................................................................................................7 Intermediate filaments ....................................................................................................8 Structure of intermediate filament proteins .............................................................8 Cellular organization of IFs ........................................................................................9 Filament assembly and dynamics ..........................................................................11 IFs and disease .........................................................................................................12 Mechanical stress and keratin IFs ..........................................................................13 Optimizing structural support during wound repair and cell migration .............13 The plakin protein family of cytoskeletal linker proteins .........................................14 Plectin - the optimally designed cytoskeletal linker protein ....................................16 Structure and function of plectin .............................................................................16 Plectin and disease ...................................................................................................19 Plectin deficiency in mice .........................................................................................21 Molecular cell biology of the skin ...................................................................................22 Histology of the epidermis ...........................................................................................22 Epidermal homeostasis ...............................................................................................22 Desmosomes .................................................................................................................24 Hemidesmosomes ........................................................................................................25 Skin wound healing ......................................................................................................27 Molecular events regulating keratinocyte migration ................................................28 TABLE OF CONTENTS V The contribution of α6β4 integrin to the development of squamous cell carcinoma .......................................................................................................................29 Generation of conditional knockout mice by Cre-mediated recombination .............29 Aim of Thesis .........................................................................................................................32 Results ....................................................................................................................................34 PART I - The conditional knockout of plectin in stratified epithelia ..........................34 Generation of mice with a conditional deletion of plectin in stratified epithelia ...34 Inactivation of the plectin gene in mouse skin leads to severe skin fragility .......35 Highly efficient reduction of plectin levels by K5-controlled Cre expression. ......38 Unaltered epidermal stratification and differentiation in K5-Cre KO mice ...........41 Plectin-deficiency does not affect proliferation and survival of keratinocytes .....45 Inactivation of the plectin gene in stratified mouse epithelia leads to early postnatal death, caused by severe blistering of the oral epithelium .....................46 Inducible knockout of plectin in adult mouse skin leads to increased epidermal fragility ............................................................................................................................48 PART II – Plectin as a regulator of keratinocyte cytoarchitecture and migration. ..50 Molecular characterization of an immortalized mouse keratinocyte cell line ......50 Plectin links keratin filaments alternatively to integrin α6β4 or actin filaments ...52 Plectin-deficient keratinocytes display enhanced spreading along with reduced integrin ß4 clustering ....................................................................................................57 Faster migration of plectin (-/-) keratinocytes ...........................................................59 Plectin organizes the keratin network in migrating keratinocytes .........................61 Faster keratinocyte migration is driven by increased activation of Src/Erk and PKC δ signaling ..............................................................................................................69 Absence of plectin reduces desmoplakin expression levels, but does not influence desmosome formation and function .........................................................75 Part III – Biochemical characterization of plectin isoform 1c as a microtubule binding protein ...................................................................................................................81
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