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The Role of CIC in Neural Progenitors University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2017 The Role of CIC in Neural Progenitors. Rogers, Alexandra Rogers, A. (2017). The Role of CIC in Neural Progenitors. (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28322 http://hdl.handle.net/11023/3722 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY The Role of CIC in Neural Progenitors by Alexandra Rogers A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE GRADUATE PROGRAM IN NEUROSCIENCE CALGARY, ALBERTA APRIL, 2017 © Alexandra Rogers 2017 Abstract Oligodendrogliomas (ODG) are brain tumours with distinct genetic hallmarks, including 1p/19q chromosomal co-deletion and IDH1/2 mutation. The gene encoding Capicua (CIC), on chr19q13.2, has been identified as mutated in ODGs with 1p/19q loss and IDH1/2 mutation, a rare genetic signature. Mutation of the retained 19q CIC allele is likely functionally important, but its contribution to ODG biology is unknown. To characterize the temporal and spatial expression of CIC in the normal mouse cerebrum, I examined CIC expression throughout development. CIC is expressed at a time and place in development in which it may influence cortical progenitors. To determine if CIC loss affects proliferation or differentiation of neural progenitors, CIC biologic functions were examined using loss-of-function approaches in vitro and in vivo. CIC loss was increased proliferation and cell growth, and effected progenitor differentiation and migration. Thus, my data supports a role for CIC in regulating processes in neural progenitors that are relevant to cancer. ii Preface Contributions to thesis work: Alexandra Rogers performed, analyzed, and interpreted the majority of the experiments with the support of her supervisors Dr. Gregory Cairncross and Dr. Jennifer Chan. Dr. Rajiv Dixit performed all in utero electroporation techniques for this work. Dr. Samuel Lawn performed the preliminary CIC shRNA knockdown experiments using p53 -/- mouse neural stem cells. iii Acknowledgements To begin, I have to thank the Alberta Cancer Foundation and all of their donors for investing in my research, and providing me with the funding necessary to get this project off the ground. I would like to thank my supervisor Dr. Gregory Cairncross for providing me with the opportunity to pursue this research, and for trusting a student with no previous training, who came out of nowhere at a brain cancer awareness day event to talk about your work, with such an interesting and novel project. If you had not offered me a volunteer position in your lab that fateful day in 2010, my life would be completely different. A massive thank you goes out to my supervisor Dr. Jennifer Chan, who spent countless hours working with me on this project; answering my (ridiculous) questions about all things science, helping me troubleshoot all of the experiments I couldn’t figure out on my own, infecting me with your excitement over good results, being proud of my achievements, and just generally pushing me to work harder, ask bigger questions, and strive for greater successes. It was a long road to get to this point, but we made it! Thank you to my committee members, Dr. Savraj Grewal and Dr. Carol Schuurmans, for being excited about my work, and for guiding my research and constantly providing excellent suggestions and input on everything I had to show you. I could not have done all this work without the help and instruction of all of my fantastic lab mates in the Chan/Cross lab emporium. Shout outs and thank yous to: Christian (aka Sunshine), for putting up with all of my annoying questions and for always having just the right answer; Rajiv, for being an absolute superstar, and my rock in the last few months of frantic data collection and thesis writing; Sam, for being a font of knowledge for all thing cloning, and for iv always eating any food I brought in for the lab, no matter what; Lori, Jessica, and Karol, for listening to my complaints at morning coffee, and always being exceptionally positive and supportive towards me; and to Mike, for keeping me sane and grounded throughout this crazy process. As well, a shout out to previous lab mates and past and present summer students for all of your help and for teaching me how to teach (Western Blots, at least.) A big thank you to my class of 2017 Leaders in Medicine crew for spending time with me in the library, editing my thesis (I’m looking at you Jason!), and generally being a ridiculously supportive group of amazing cheerleaders and friends. I can’t wait to spend the next three years getting into all sorts of trouble with you crazy kids! To Kyle: thank you for not saying ‘I told you so’ (even though I know you wanted to so bad!) Thank you for listening to my nonsense and actually caring about it even if it was ridiculous. Thank you for keeping me fed post working in the lab all weekend, for never being mad when I had to put science over you, and for being truly understanding and supportive of my dreams. Last but not least, thank you to the people I wouldn’t be here without: my family. I literally could not have done this without your constant, unwavering belief in my ability to succeed at anything I truly put my mind to. Thank you for instilling in me a love of learning, the confidence to set my sights on a goal, and the work ethic to persist until I achieve it. I can’t even articulate how much your love and support means to me, except to repeat what I said above: I literally could not have done this without Heather, Floyd, and Ian Rogers. You guys are amazing, thank you for everything! v Dedication I dedicate this thesis to everyone who has believed in me and supported me over the years, most especially my parents, Heather and Floyd Rogers. vi Table of Contents Abstract ................................................................................................................................ i Preface................................................................................................................................. ii Acknowledgements ............................................................................................................ iii Dedication ............................................................................................................................v Table of Contents .............................................................................................................. vii List of Tables ..................................................................................................................... ix List of Figures and Illustrations ...........................................................................................x List of Symbols, Abbreviations and Nomenclature .......................................................... xii CHAPTER 1: INTRODUCTION ........................................................................................1 1.1 Cortical organization and development .........................................................................1 1.1.1 Cortical cell types and structure ..............................................................................2 1.1.2 Events in forming the Neocortex ............................................................................3 1.1.3 Timing of cerebral cortical development ................................................................6 1.2 Regulators of cell fate ....................................................................................................7 1.2.1 Extrinsic controls ....................................................................................................7 1.2.2 Intrinsic controls ...................................................................................................10 1.3 Capicua (CIC) ..............................................................................................................12 1.3.1 CIC structure .........................................................................................................12 1.3.2 CIC interactions and regulation ............................................................................14 1.3.3 CIC biologic functions – Lessons from Drosophila .............................................16 1.3.4 CIC in mice and humans .......................................................................................18 1.3.5 CIC as a cancer gene .............................................................................................19 1.4 Developmental aspects of oligodendrogliomas ...........................................................20 1.4.1 Links between oligodendrocyte precursor cells and oligodendrogliomas ............21 1.5 Hypothesis & Aims ......................................................................................................22 1.6 Figures and Figure Legends .........................................................................................23 CHAPTER 2: MATERIALS AND METHODS ...............................................................29
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