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Dlx Homeobox Transcriptional Regulation of Crx and Otx2 Gene Expression During Vertebrate Retinal Development

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Dlx Homeobox Transcriptional Regulation of Crx and Otx2 Gene Expression During Vertebrate Retinal Development DLX HOMEOBOX TRANSCRIPTIONAL REGULATION OF CRX AND OTX2 GENE EXPRESSION DURING VERTEBRATE RETINAL DEVELOPMENT by Vanessa Indira Pinto A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfilment of the degree requirements for MASTER OF SCIENCE Department of Biochemistry & Medical Genetics University of Manitoba Winnipeg Copyright © 2010 Vanessa Indira Pinto Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-70190-4 Our file Notre référence ISBN: 978-0-494-70190-4tdm NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives 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 le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, 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 this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. Table of Contents Acknowledgements ......................................................................................................................... v Abstract ......................................................................................................................................... vii List of Abbreviations ..................................................................................................................... ix List of Tables ................................................................................................................................. xi List of Figures ............................................................................................................................... xii List of Copyrighted Material for which Permission was Obtained ............................................. xiv 1. Introduction ................................................................................................................................. 1 1.1 RETINA: STRUCTURE AND DEVELOPMENT .............................................................. 1 1.1.1 Anatomical structure of retina ....................................................................................... 1 1.1.2 Retinal Function ............................................................................................................. 4 1.1.3 Murine Retinal Development ......................................................................................... 5 1.1.4. Retinogenesis ................................................................................................................ 6 1.1.5 Competency ................................................................................................................... 7 1.1.6. Photoreceptor Development........................................................................................ 11 1.2 DLX GENES IN DEVELOPMENT ................................................................................... 13 1.2.1 Dlx gene family ............................................................................................................ 13 1.2.2 Expression and function of Dlx Genes......................................................................... 14 1.2.3 Dlx1/2 genes in retina and forebrain ............................................................................ 15 1.3 OTX GENES (Pinto, 2010) ................................................................................................ 19 1.3.1 Family .......................................................................................................................... 19 ii 1.3.2 Expression .................................................................................................................... 22 1.3.3 Function ....................................................................................................................... 23 1.3.4 Otx genes in retina: Otx2 and Crx ................................................................................ 23 1.4 Hypothesis and Research Aims .......................................................................................... 30 2. Materials and Methods .............................................................................................................. 31 2.1. Animal and tissue preparation ........................................................................................... 31 2.2. Tissue embedding and sectioning ...................................................................................... 32 2.3 Histological staining and immunofluorescence (IF) ........................................................... 33 2.6. Electrophoretic Mobility Shift Assays (EMSA) ................................................................ 40 2.7. Luciferase Reporter Assays ............................................................................................... 42 2.8. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)..................................... 44 3. Results ....................................................................................................................................... 46 3.1 Expression Patterns of CRX and OTX2 in the Developing Retina .................................... 46 3.1.1. Dual Immunoflurorescence (DIF)-OTX2 and CRX ................................................... 50 3.1.2. DIF – OTX2 and DLX2 .............................................................................................. 52 3.1.3. DIF – CRX and other markers .................................................................................... 54 3.1.4. Gain-of-Function......................................................................................................... 57 3.2. DLX2 Binds to the Otx2 and Crx Gene Promoters............................................................ 61 3.2.1. DLX2 Binds to the Otx2 and Crx Promoters in vivo .................................................. 61 3.2.2. DLX2 Binds to the Otx2 and Crx Promoters in vitro ................................................. 64 iii 3.3. DLX2 regulates Otx2 and Crx expression in vivo and in vitro .......................................... 67 3.3.1. DLX1 and DLX2 repress Otx2 and Crx expression in vivo ........................................ 67 3.3.2. DLX2 regulates Crx expression in vitro ..................................................................... 68 4. Discussion ................................................................................................................................. 70 4.1. DLX2 restricts Otx2 and Crx gene transcript expression and, to a lesser extent, protein expression. ................................................................................................................................ 70 4.2. The DLX2 transcription factor binds to the promoters of retinal genes Otx2 and Crx ..... 74 iv ACKNOWLEDGEMENTS The lessons learned through the course of this degree were not in science alone, and those are the lessons that are the most worthwhile. Here is where I raise my glass to those who have taught me the most. First, many thanks to the University of Manitoba, Manitoba Institute of Cell Biology, CancerCare Manitoba Foundation and Manitoba Institute of Child Health for providing the space and funds to forge memorable experiences and relationships. To my committee members and other staff thank you for your guidance and advice. To my supervisor, Dr. David Eisenstat; if there was ever an example of a real-life superhero, you would be it. Not only do you save lives, but I've seen you move faster than a speeding bullet and leap over piles of articles in a single bound. There are very few people in this world who are willing to „celebrate the unconventional‟, who truly have your back and a box of Kleenex at the ready. I am proud to say that I had you as a mentor and have become a better scientist and person because of it. To borrow a chuckle from your catalogue, you really are a SUPER-visor. I will not acknowledge my lab mates as such, because they are not co-workers but family. So, to my lab family, I turn to Lionel Richie to explain: “As we go down life’s lonesome highway, seems
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