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Iroquois Homeobox 3 Is an Essential Transcription Factor in the Maintenance of Proper Electrical Propagation and Development of the Ventricular Conduction System

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Iroquois Homeobox 3 Is an Essential Transcription Factor in the Maintenance of Proper Electrical Propagation and Development of the Ventricular Conduction System Iroquois Homeobox 3 is an Essential Transcription Factor in the Maintenance of Proper Electrical Propagation and Development of the Ventricular Conduction System by Anna Rosen A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Physiology University of Toronto © Copyright by Anna Rosen 2010 Iroquois Homeobox 3 is an Essential Transcription Factor in the Maintenance of Proper Electrical Propagation and Development of the Ventricular Conduction System Anna Rosen Master of Science Department of Physiology University of Toronto 2010 ABSTRACT The specialized myocytes of the ventricular conduction system (VCS) coordinate ventricular contraction and are critical for efficient pumping by the heart. Impaired VCS conduction is characteristic of inherited forms of cardiac conduction disorders. Here we show that the Iroquois homeobox 3 (Irx3) transcription factor is preferentially expressed in the developing and mature VCS. Loss of Irx3 in mice results in slowed VCS conduction and prolonged QRS duration with right bundle branch block, caused by reduction (42%) in VCS-specific connexin 40 (Cx40) expression and VCS fiber hypoplasia, absent in littermate controls. Therefore, we show that the role of Irx3 in the heart is two-fold, whereby Irx3 (1) indirectly regulates Cx40 gene expression, by repressing a repressor of Cx40 transcript, and (2) controls VCS maturation, possibly in an Nkx2-5-dependent manner. To our knowledge, this is the first report of a role for Irx3 in regulating the development and function of the VCS. ii ACKNOWLEDGMENTS I would first like to thank my supervisor Dr. Peter Backx whose attentiveness, guidance and expertise added considerably to my graduate experience. Peter’s contagious passion for science, combined with his excellence in teaching allowed me to gain invaluable experience in the lab aiding in my development as a young scientist. I would also like to thank Peter for his advice and support of my future interests in a veterinary career which combined with his great sense of humour made my graduate studies both valuable and enjoyable. I would also like to thank my committee members Dr. Scott Heximer and Dr. Peter Pennefather for their insight and stimulating suggestions and discussions. Their guidance throughout this process has been outstanding. I am especially indebted to my collaborator and committee member, Dr. Chi-Chung Hui, for his new prospective on the project allowing it to proceed in new and exciting directions which have greatly contributed to the quality of this thesis. I would like to show my gratitude to all former and current members of Dr. Backx’s laboratory, which have made my working environment enjoyable, supportive and productive: Kyoung-Han Kim, Dr. Sanja Beca, Dr. Roozbeh Sobbi, Dr. Peter Helli, Dr. Robert Rose, Dr. Gerrie Farman, Wallace Yang, Moniba Mirkhani, Farzad Izaddoustdar, Mark Davis, Dr. Brian Panama, Mike Sellan, Dongling Zhao, Jack Liu, Bill Liang, Roman Pekhletski, Desiree Latour, as well as Vijitha Puviindran from Dr. Hui’s lab and Brent Steer from Dr. Marsden’s lab. A very special thanks goes to my colleague and friend Kyoung-Han Kim for his limitless patience and guidance which has inspired me both personally and professionally. iii I would also like to thank the Heart and Stroke Foundation of Ontario, the Heart and Stroke/ Richard Lewar Centre of Excellence and the University of Toronto for their financial support. Lastly, I would like to thank my parents and brother for all the support they provided me throughout my life and in particular my husband and best friend, Vitali; without his love, encouragement and editing assistance, I would not have finished this thesis. Finally, I would like to thank my unborn baby for not giving me too much discomfort during the thesis writing process and for opening a new exciting chapter in my life. iv TABLE OF CONTENTS ABSTRACT………………………………………………………………………………….. ii ACKNOWLEDGEMENTS………………………………………………………………….. iii TABLE OF CONTENTS…………………………………………………………………….. v LIST OF TABLES……………………………………………………………………............ viii LIST OF FIGURES………………………………………………………………………….. ix LIST OF ABBREVIATIONS……………………………………………………………….. xi CHAPTER 1: INTRODUCTION………………………………………………………….. 1 1.1 The role of Iroquois Homeobox (Irx) genes in development and physiology………….. 2 1.1.1 Origin and expression of Irx genes……………………………………….. 2 1.1.2 The role of Iroquois homeobox genes in the mammalian heart…………. 4 1.2 The mammalian ventricular conduction system (VCS)………………………………..... 6 1.2.1 Heart conduction and VCS function……………………………………… 6 1.2.2 Molecular components of the fast conducting VCS…………………….... 8 1.2.3 Development of the murine VCS…………………………………………. 11 1.2.4 Disorders of the cardiac conduction system……………………………… 14 1.3 Synopsis………………………………………………………………………................. 17 TECHNICAL CONTRIBUTION & ACKNOWLEDGEMENT………………………... 19 CHAPTER 2: MATERIALS & METHODS……………………………………………… 20 2.1 Experimental Animals…………………………………………………………………... 21 2.2 X-galactosidase staining………………………………………………………………… 22 2.3 In-vivo Electrocardiogram (ECG)……………………………………………………...... 22 2.4 Intracardiac Catheterization…………………………………………………………....... 23 2.5 Optical imaging and analysis…………………………………………………………..... 25 2.5.1 Heart perfusion and optical imaging……………………………………… 25 2.5.2 Signal processing and data analysis………………………………………. 26 2.6 Ex-vivo electrocardiogram……………………………………………………………..... 28 2.7 VCS fiber conduction velocity…………………………………………………………... 29 v 2.8 Laser Capture Microdissection (LCM)…………………………..…………………….. 30 2.8.1 Heart preparation and sectioning………………………………………..... 30 2.8.2 Dehydration and LCM…………………………………………………..... 30 2.8.3 RNA Isolation and cDNA synthesis……………………………………… 32 2.8.4 Quantitative Real-Time PCR……………………………………………... 33 2.9 Isolation of Neonatal Mouse Ventricular Myocytes………………..……………….…. 34 2.10 Adenoviral Construct Generation……………………………………………………… 35 2.11 Fiber imaging and quantification of EGFP fluorescence………………………………. 36 2.12 Statistical analysis……………………………………………………………………… 37 CHAPTER 3: RESULTS…………………………………………………………………... 38 3.1 Irx3 is preferentially expressed in the developing and mature ventricular conduction system................................................................................................................................ 39 3.2 Phenotype of Irx3 deficient mice…...…………………………………………………… 42 3.2.1 Altered ventricular activation in Irx3-/- mice……………………………… 42 3.2.2 Increased His-ventricular conduction time in Irx3-/- mice………………… 46 3.2.3 Irx3-/- mice have functional right bundle branch block………………..….. 48 3.2.4 Irx3-/-;Cx40+/EGFP reporter mice show comparable phenotype to Irx3-/- mice………………………………………………………………………... 52 3.2.5 Slowed VCS fiber conduction in Irx3-/-;Cx40+/EGFP mice…………..……. 54 3.3 Irx3 maintains normal VCS conduction by indirectly regulating Cx40 gene expression. 56 3.3.1 Loss of Irx3 results in decreased Cx40 mRNA expression in VCS cells…. 56 3.3.2 Cx40-/- mice have a conduction phenotype similar to Irx3-/- mice………… 59 3.3.3 Transcriptional regulation of Cx40 gene expression by Irx3........................ 61 3.4 Irx3 maintains proper ventricular activation by regulating ventricular conduction system fiber development…...………………………………………………….……….. 63 3.4.1 Decreased fiber complexity and Cx40 promoter activity in adult Irx3 deficient mice……….……….……………………………………………. 63 3.4.2 Decreased fiber complexity in postnatal day 4 (P4) and 0 (P0) of Irx3 deficient mice………………………………..…………………………….. 67 3.4.3 P0 Irx3-/- cardiomyocyte show decreased Cx40 mRNA expression………. 70 3.4.4. Loss of VCS complexity in Irx3 deficient mice is independent of Cx40 levels…........................................................................................................ 71 3.5 Synopsis…………………………………………………………………………………. 73 vi CHAPTER 4: DISCUSSION……………………………………………………………..... 74 4.1 Irx3 is the first known transcription factor to be preferentially expressed in the developing and mature ventricular conduction system (VCS).......................................... 75 4.2 Loss of Irx3 results in altered ventricular activation......................................................... 77 4.3 Irx3 controls VCS conduction by indirectly regulating Cx40 expression………………. 83 4.4 Irx3 in required for postnatal VCS development………………………………………... 90 4.4.1 Decreased VCS complexity in Irx3 deficient mice contributes to its VCS conduction defect ………………………………………………………… 90 4.4.2 Irx3 may regulate VCS development in an Nkx2-5 dependent manner…… 92 4.5 Clinical implications…………………………………………………………………….. 95 4.6 Synopsis…………………………………………………………………………………. 98 CHAPTER 5: FUTURE DIRECTIONS…………………………………………………... 100 5.1 Understanding the indirect mechanism of Cx40 regulation by Irx3…………………….. 101 5.2 Understanding the developmental role of Irx3………………………………………….. 103 5.2.1 Prenatal assessment of VCS morphology in Irx3-/- and WT mice………… 103 5.2.2 Determining the underlying cause of hypoplasia in Irx3-/- mice…………... 103 CHAPTER 6: REFERENCES……………………………………………………………... 105 vii LIST OF TABLES Table 2.1 - List of Oligonucleotide Primers for Quantitative RT-PCR…………………... 34 Table 3.1 - Quantification of Irx3+/+, Irx3+/- and Irx3-/- mouse ECG parameters………… 45 viii LIST OF FIGURES CHAPTER 1: INTRODUCTION FIGURES Figure 1.1 - Iroquois family in Drosophila and mammalian genomes………………… 3 Figure 1.2 - Mammalian cardiac conduction system and mouse electrocardiogram……. 8 Figure 1.3 - Connexin channel expression pattern……………………………………….. 10 Figure 1.4 - Impulse
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