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CHARACTERIZATION of the CASZ1-DEPENDENT MECHANISMS ESSENTIAL for CARDIOMYOCYTE DEVELOPMENT Kerry M. Dorr a Dissertation Submitte

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CHARACTERIZATION of the CASZ1-DEPENDENT MECHANISMS ESSENTIAL for CARDIOMYOCYTE DEVELOPMENT Kerry M. Dorr a Dissertation Submitte CHARACTERIZATION OF THE CASZ1-DEPENDENT MECHANISMS ESSENTIAL FOR CARDIOMYOCYTE DEVELOPMENT Kerry M. Dorr A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Genetics and Molecular Biology in the School of Medicine. Chapel Hill 2015 Approved by: Frank Conlon Terry Magnuson Li Qian Joan Taylor Andy Wessels © 2015 Kerry M. Dorr ALL RIGHTS RESERVED ii ABSTRACT Kerry M. Dorr: Characterization of the Casz1-Dependent Mechanisms Essential for Cardiomyocyte Development (Under the direction of Frank L. Conlon) The heart is one of the first structures to form during development and is required for embryonic growth and survival. The four-chambered mammalian heart arises from a series of complex processes during embryonic development that includes the specification and differentiation of the different cardiac cell types within the heart, proliferation, and morphological movements of the early heart fields. Early development of the heart is governed by hyperplastic growth in which cardiac cells undergo mitogen- dependent activation during the G1-phase of the cell cycle. Though numerous growth factor signals have been shown to be required for cardiomyocyte proliferation, genetic studies have only identified a limited number of transcription factors that act to regulate the entry of cardiomyocytes into S-phase. Casz1 is an evolutionarily conserved transcription factor that is essential for heart development; however, there are vast deficiencies in our understanding of the mechanism by which Casz1 regulates aspects of cardiac development. Here we report that Casz1 is expressed in, and gives rise to, cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is required for the proper development and growth iii of the cardiac chambers. We further demonstrate that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to severe cardiac hypoplasia, ventricular septal defects, and a decrease in cardiomyocyte cell number. Additionally, we report that the loss of Casz1 leads to a prolonged or arrested S-phase, a decrease in DNA synthesis, an increase in phosphorylated-Rb, and a concomitant decrease in the cardiac mitotic index. Taken together these studies establish a role for Casz1 in mammalian heart development and cardiomyocyte cell cycle progression. iv To my wonderful boys, I couldn’t have done it without you. Thank you for illuminating my life. v ACKNOWLEDGEMENTS There are many people that have been critical to the success of my graduate studies. I would first like to thank current and past members of the Conlon Lab for helpful discussions, advice, support, and technical know-how: Kathleen Christine, Chris Showell, Panna Tandon, Erin Kaltenbrun, Lauren Kuchenbrod, Lauren Waldron, Nirav Amin, Stephen Sojka, Kerry Dorr, Marta Charpentier, Chris Slagle, Michelle Villasmil, Leslie Kennedy, and Carrie Wilczewski. Special thanks to Chris Showell for being an excellent mentor and friend my first few years in the lab, and to Erin Kaltenbrun for being my lab BFF. This experience would not have been the same without her sarcastic and charming wit. I cannot thank or acknowledge Frank Conlon enough. He has been so supportive of my career and of me as a person. Frank has a remarkable ability to build me up when I am down and push me when I need it. He has been enthusiastic throughout this very difficult and time-consuming project, always available when I needed to bounce ideas around, and has allowed me an enormous amount of independence. This mentoring has helped me to grow as a scientist and a professional and for that I am forever grateful. It is also a joy to work for someone that truly cares about the people in his lab, not only from a scientific perspective, but also on a personal level. For this reason, the morale in the Conlon Lab is extremely high and there is a lot of camaraderie, qualities that have made coming to work a pleasure even when science wasn’t going so well. vi I would also like to thank my committee members Terry Magnuson, Li Qian, Joan Taylor, and Andy Wessels. I am so grateful for the mentorship and support that I have received from each of them. One of the things that drew me to UNC was the faculty commitment to good training, and my committee has demonstrated this commitment throughout my graduate experience. I am extremely appreciative for their insights and helpful discussions on my work. Finally, I would like to thank my family and friends for their support, encouragement, and friendship. My parents have given me their unwavering support and have always made me feel loved and appreciated. My father is an amazing, well- accomplished scientist and I think it was all of those Saturdays I spent with him at work playing with Eppendorf tubes that made me gain a passion for science. I would especially like to thank my wonderful husband, Mark, whose companionship, wisdom, patience, tolerance, and love have uplifted me every day that we have been together. We rode the bus together our very first day of graduate school and have been inseparable ever since. I also thank our wonderful baby, Maxwell, who has uplifted my life to heights I never thought I would attain and is truly the best developmental biology experiment I ever undertook. Thanks also to our other baby boy, “soon to be named”. I can’t wait to meet you. vii TABLE OF CONTENTS LIST OF FIGURES ......................................................................................................... xii LIST OF TABLES ........................................................................................................... xv LIST OF ABBREVIATIONS ........................................................................................... xvi CHAPTER 1: INTRODUCTION The cardiomyocyte cell cycle ................................................................................ 3 Cardiomyocyte cell cycle control and growth ........................................................ 5 Proliferation ................................................................................................ 6 Binucleation ............................................................................................... 9 Hypertrophy ............................................................................................. 12 Growth factors and signaling pathways that regulate proliferation...................... 15 Hippo ....................................................................................................... 15 Wnt .......................................................................................................... 17 Insulin-like growth factor .......................................................................... 20 Neuregulin ............................................................................................... 21 Periostin ................................................................................................... 22 Fibroblast Growth Factor ......................................................................... 23 MicroRNAs regulate cardiomyocyte proliferation ................................................ 26 Transcription factors that regulate cardiomyocyte proliferation ........................... 28 Foxp1 ....................................................................................................... 28 viii Jumonji .................................................................................................... 29 Hopx ........................................................................................................ 30 Meis1 ....................................................................................................... 31 Tbx1 ......................................................................................................... 32 Tbx5 ......................................................................................................... 32 Tbx20 ....................................................................................................... 33 Casz1-Dependent Mechanisms ............................................................... 34 Dissertation Goals .............................................................................................. 35 References ......................................................................................................... 42 CHAPTER 2: CASZ1 IS REQUIRED FOR CARDIOMYOCYTE G1-TO-S PROGRESSION DURING MAMMALIAN CARDIAC DEVELOPMENT INTRODUCTION ................................................................................................ 77 MATERIALS AND METHODS ............................................................................ 79 RESULTS ........................................................................................................... 88 Casz1 is expressed in the developing myocardium ................................. 88 Casz1-expressing cells give rise to first and second heart field derivatives ................................................................................................ 90 Casz1 is essential for cardiac development ............................................. 91 Casz1 is required for growth of the cardiac chambers ............................. 93 Casz1 embryonic nulls phenocopy Casz1f/f;Nkx2.5Cre/+ embryos ............ 93 Casz1 is essential in the second heart field ............................................
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