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University of London Thesis REFERENCE ONLY UNIVERSITY OF LONDON THESIS Degree pWvO Y e a r Name of Author ^ COPYRIGHT This is a thesis accepted for a Higher Degree of the University of London. It is an unpublished typescript and the copyright is held by the author. All persons consulting the thesis must read and abide by the Copyright Declaration below. COPYRIGHT DECLARATION I recognise that the copyright of the above-described thesis rests with the author and that no quotation from it or information derived from it may be published without the prior written consent of the author. LOANS Theses may not be lent to individuals, but the Senate House Library may lend a copy to approved libraries within the United Kingdom, for consultation solely on the premises of those libraries. Application should be made to: Inter-Library Loans, Senate House Library, Senate House, Malet Street, London WC1E 7HU. REPRODUCTION University of London theses may not be reproduced without explicit written permission from the Senate House Library. Enquiries should be addressed to the Theses Section of the Library. Regulations concerning reproduction vary according to the date of acceptance of the thesis and are listed below as guidelines. A. Before 1962. Permission granted only upon the prior written consent of the author. (The Senate House Library will provide addresses where possible). B. 1962 - 1974. In many cases the author has agreed to permit copying upon completion of a Copyright Declaration. C. 1975 - 1988. Most theses may be copied upon completion of a Copyright Declaration. D. 1989 onwards. Most theses may be copied. This thesis comes within category D. This copy has been deposited in the Library of This copy has been deposited in the Senate House Library, Senate House, Malet Street, London WC1E 7HU. C:\Documents and Settings\lproctor\Local Settings\Temporary Internet Files\OLK8\Copyright - thesis (2).doc Human macular gene expression b y Daniel Mark Homan submitted for the degree of Doctor of philosophy in Genetics UCL Division of Molecular Genetics Institute o f Ophthalmology, University College London UMI Number: U592054 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592054 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The human macula is essential for precise vision. It contains many more cone photore­ ceptors than the peripheral retina, especially in the fovea. Cones are known to express specific opsins and other proteins that form part of the phototransduction cascade. However, relatively little is known about retinal macular gene expression compared with the rod-rich peripheral retina. I obtained human donor eyes and used foveo-macular and macular punches and sections of peripheral retina to study differential gene expres­ sion. I combined multiple microarray experiments with quantitative PCR, statistical, and bioinformatic analyses. I identified several known and previously unidentified retinal genes that are more abundant in the macula. I went on to characterize proteins encoded by histone deacetylase 9 and the morpheus gene family. Both were expressed in the human macula, especially in the photoreceptors. Several other genes also provided insight into the mechanisms of precise vision and its maintenance. Genes identified by this approach are excellent candidates for macular disease. 1 Contents 1 Introduction 16 1.1 R e tin a .................................................................................................................... 18 1.1.1 Retinal pigment epithelium ................................................................... 21 1.1.2 Neural r e t i n a .......................................................................................... 22 1.1.3 P hotoreceptors....................................................................................... 23 1.1.4 Photoreceptor connections ................................................................... 26 1.1.5 Bipolar cells .......................................................................................... 27 1.1.6 Ganglion cells ...................................................................................... 28 1.1.7 Horizontal c e lls ...................................................................................... 30 1.1.8 Amacrine c e l l s ...................................................................................... 31 1.2 Phototransduction ................................................................................................ 32 1.2.1 Cones versus rods ................................................................................ 33 1.2.2 Photoreceptor tu rn o v er ......................................................................... 35 1.3 Macular gene expression .................................................................................... 35 1.3.1 Serial analysis of gene expression ...................................................... 36 1.3.2 Macular disease....................................................................................... 38 1.3.3 Age-related macular degeneration ...................................................... 46 1.3.4 Functional g e n o m ic s ............................................................................. 50 1.4 O bjectives ............................................................................................................. 52 1.5 Results................................................................................................................... 53 1.6 Discussion ............................................................................................................. 56 2 CONTENTS 3 1.7 Conclusions ........................................................................................................ 58 2 Methods 59 2.1 Tissue procurement .......................................................................................... 59 2.2 Dissection ........................................................................................................... 60 2.3 RNA ex tractio n ................................................................................................. 60 2.3.1 Handling R N A .................................................................................... 60 2.3.2 Isolation of RNA from Small Quantities of Tissue ......................... 61 2.3.3 RNA gel electrophoresis .................................................................... 64 2.4 Analysis of foveal and peripheral retinal m R N A .......................................... 66 2.5 Construction of cDNA library ....................................................................... 67 2.6 Library screening .............................................................................................. 67 2.7 Microarray ........................................................................................................ 68 2.8 Quantitative P C R .............................................................................................. 73 2.9 Tissue and antibody resources ....................................................................... 76 2.10 Tissue culture ..................................................................................................... 77 2.11 Enzyme linked immuno-sorbent assay (ELISA ) .......................................... 79 2.11.1 C o a tin g ................................................................................................. 79 2.11.2 Blocking .............................................................................................. 79 2.11.3 Sample .................................................................................................. 79 2.11.4 W ash ..................................................................................................... 80 2.11.5 Conjugate .............................................................................................. 80 2.11.6 W ash ..................................................................................................... 80 2.11.7 Substrate .............................................................................................. 81 2.11.8 Stop ........................................................................................................ 81 2.12 Western blotting .................................................................................................. 81 2.13 Immunofluorescence ........................................................................................ 83 2.13.1 Cell c u ltu re ........................................................................................... 83 2.13.2 Retinal sections .................................................................................... 84 CONTENTS 4 2.13.3 Imaging ................................................................................................... 85 2.14 Antisera production ............................................................................................ 86 2.15 Cloning ...............................................................................................................
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