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Mechanisms of Rod Photoreceptor Motility in Development and Following Transplantation

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Mechanisms of Rod Photoreceptor Motility in Development and Following Transplantation Mechanisms of Rod Photoreceptor Motility in Development and Following Transplantation Nozie Dominic Aghaizu UCL INSTITUTE OF OPHTHALMOLOGY Department of Molecular and Cell Therapy 2016 A thesis submitted to University College London for the degree of Doctor of Philosophy (PhD) DECLARATION I, Nozie Dominic Aghaizu, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 1 Habe nun, ach! Philosophie, Juristerei und Medizin Und leider auch Theologie Durchaus studiert, mit heißem Bemühn. Da steh ich nun, ich armer Tor! Und bin so klug als wie zuvor; – Johann Wolfgang von Goethe, “Faust” 2 ABSTRACT To establish the mature neuroepithelial tissue architecture, newborn neurons often migrate from their place of birth, usually at the apical neuroepithelial limit, towards their target destination. Even before neurons are born, the nucleus of the mitotic neuronal progenitor cell migrates within the apico-basal cellular extent in synchrony with the cell cycle (interkinetic nuclear migration or IKNM) – a migratory pattern so far only observed in mitotic epithelial progenitor cells. Rod photoreceptors, too, are born at the apical limit of the retinal neuroepithelium. They then populate a layer directly adjacent (outer nuclear layer or ONL), but not the more basal retinal layers. How rod photoreceptors become enriched specifically within the ONL is presently ill defined. Here, it was identified that rod photoreceptor somata of the developing mouse retina are constantly pushed basally (presumably caused by proximal progenitor IKNM events). To become enriched apically within the (presumptive) ONL despite this, the post-mitotic rod photoreceptors utilised an IKNM-like migratory behaviour more typically associated with dividing cells: rod somata actively migrated apically, driven by microtubule-associated dynein I motors. Another microtubule-associated motor protein, KIF1A, acts as a molecular brake during basal displacement, preventing ectopic basal positions. Rod somata oscillate between apical and basal motions at least from P1 up until ~P10. Whether this involves a component of glial-guided migration could not be established beyond reasonable doubt. Nonetheless, this is the first report of an oscillatory, IKNM-like migration behaviour occurring within a post-mitotic neuronal cell population. Rod photoreceptors have also been assumed to migrate into the adult neural retina following sub-retinal transplantation for cell-replacement therapeutic purposes, although this has not been directly observed. Here, time-lapse footage for the first time showed rod photoreceptors migrating from the sub-retinal space into the host retina. This supports the notion that photoreceptor cell replacement therapy could become a clinically viable treatment option. 3 ACKNOWLEDGEMENTS I would like to thank my supervisors Professor Rachael Pearson and Professor Robin Ali for awarding me the opportunity to work on this challenging, yet interesting, project and for creating a highly stimulating research milieu. I am especially grateful to Professor Rachael Pearson for her continuous academic support, the insightful research feedback and guidance throughout my PhD. My sincerest gratitude also goes to Dr. Katherine Warre-Cornish, who’s excellent PhD project set the groundwork for my own project. Helping me reach my full research potential, I must also include special mentions for Dr. Christopher Thrasivoulou, Daniel Ciantar and Tim Robson for their assistance during microscopy image acquisition, Professor Matteo Carandini, Martha Robinson and Paul Waldron for their programming and data analysis expertise, Dr. Alexander Smith and Dr. Anastasios Georgiadis for molecular biology related advice, as well as Professor Rachael Pearson, Yanai Duran, Dr. Ayad Eddaoudi and Robert Sampson for their support during experiments. I would also like to thank all other colleagues and friends I have made throughout my PhD, both within and outside of this group, who have made the past years a truly unforgettable experience. I dedicate this thesis to my family, especially my parents, Dominic Nwabugwu and Maria Azucena, who have gone above and beyond themselves to provide me and my sister, Grazia Chidi, with the best opportunities. 4 TABLE OF CONTENTS DECLARATION ............................................................................................................. 1 ABSTRACT ..................................................................................................................... 3 ACKNOWLEDGEMENTS ............................................................................................ 4 TABLE OF CONTENTS ................................................................................................ 5 LIST OF FIGURES ........................................................................................................ 9 LIST OF TABLES ........................................................................................................ 15 LIST OF MOVIES ........................................................................................................ 17 LIST OF COMMON ABBREVIATIONS .................................................................. 18 CHAPTER I. INTRODUCTION ................................................................................. 20 1.1. The mammalian eye .......................................................................................... 21 1.1.1. Overview....................................................................................................... 21 1.1.2. Structure and function of the eye.................................................................. 21 1.1.3. Structure of the retina .................................................................................. 23 1.1.4. Photoreceptors ............................................................................................. 26 1.1.5. Function of photoreceptors .......................................................................... 28 1.1.6. Müller glia .................................................................................................... 32 1.1.7. Functions of Müller glia ............................................................................... 34 1.2. Eye development ................................................................................................ 39 1.2.1. Overview....................................................................................................... 39 1.2.2. Retinal progenitor cells and proliferation ................................................... 40 1.2.3. Principles of cell fate specification in the developing retina ....................... 42 1.2.4. Rod photoreceptor determination and differentiation ................................. 45 1.2.5. Müller glia determination and differentiation ............................................. 48 1.3. Migration in the central nervous system ......................................................... 54 1.3.1. Overview....................................................................................................... 54 1.3.2. Interkinetic nuclear migration (IKNM) ........................................................ 55 1.3.3. Somal translocation...................................................................................... 58 1.3.4. Multipolar migration .................................................................................... 62 1.3.5. Glial-guided migration ................................................................................. 65 1.3.6. Tangential migration .................................................................................... 69 1.3.7. Mechanisms of neuronal migration ............................................................. 71 5 1.4. Transplantation ................................................................................................. 89 1.4.1. Overview....................................................................................................... 89 1.4.2. Retinal disease.............................................................................................. 89 1.4.3. Therapeutic avenues for retinal diseases ..................................................... 90 1.4.4. The transplantation of donor derived photoreceptor cells........................... 93 1.4.5. The transplantation of stem cell derived photoreceptor cells ...................... 96 1.4.6. Potential mechanisms involved in the integration and migration of transplanted rod photoreceptor cells ....................................................................... 97 AIMS AND OBJECTIVES ........................................................................................ 101 CHAPTER II. MATERIALS AND METHODS ...................................................... 103 2.1. Methods of molecular biology ........................................................................ 103 2.1.1. General cloning techniques ........................................................................ 103 2.1.2. Specific plasmid DNA design ..................................................................... 109 2.1.3. Recombinant AAV ...................................................................................... 114 2.1.4. RNA analysis .............................................................................................. 118 2.2. Animals ............................................................................................................
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