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A T-Box Protein Interacting with the TCF Transcriptional Switch of Wnt Signaling in Xenopus Dorsal Axis Development By

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A T-Box Protein Interacting with the TCF Transcriptional Switch of Wnt Signaling in Xenopus Dorsal Axis Development By A T-box Protein Interacting with the TCF Transcriptional Switch of Wnt Signaling in Xenopus Dorsal Axis Development by Yaxuan Yang A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular, Cellular and Developmental Biology) in the University of Michigan 2014 Doctoral Committee: Professor Kenneth M. Cadigan, Chair Professor Steven E. Clark Professor Robert J. Denver Professor Diane M. Robins © Yaxuan Yang All rights reserved 2014 DEDICATION To my beloved family ii ACKNOWLEDGEMENTS First and foremost, I would like to thank my tremendous advisor Professor Kenneth M. Cadigan. Over the past 6 years, Ken has been offering me constant guidance and help on every aspect of my scientific development, including making strategic decisions about experiments when things were not going well, teaching me how to ask the right questions and how to handle questions effectively, telling us the secret “boy and girl” theory to organize a talk, giving me advice on improving my oral presentation and writing, and sharing his own experiences during his career development. Besides being a critical, smart and diligent scientist, Ken is also very nice to students. He is always patient and supportive when I tell him my difficulties. Also, Ken’s positive attitude has deeply influenced my view about life, which I will be always grateful for. I would also like to thank my doctoral committee: Professor Steven E. Clark, Professor Robert J. Denver, and Professor Diane M. Robins for their scientific guidance on my research and also their support and advice for my career transition. I feel very lucky to have worked with all the awesome colleagues in Cadigan lab, Lisheng, Chandan, Aditi, Hilary, Chen, Pete and Nisa. They are always there to discuss papers, troubleshoot experiments, and do favors, such as changing buffers or stopping a digestion. In particular, it has been very stimulating discussing data with Chen. Hilary also gave me lots of advice inside and outside of science. She is a competent scientist as well as a great mom, offering me an amazing role model to learn from. I enjoyed very iii much sharing a bay with Pete during his gap year. He inspired me with lots of great ideas about research. I also want to say thanks to Chen, Hilary and Pete for proofreading my thesis. I also want to thank all the lab members in Denver lab and Miller lab for sharing frog facilities, fresh eggs and testis preps. Without their generous help, I would not be able to do many frog experiments. I also appreciate the help I got from the Csankovszki, Buttitta, Xu, and Li labs over the years. My friends in Ann Arbor and old friends elsewhere have been great company in sharing both happiness and sadness during my graduate school training. Specially, Dr. Yan Dong, thanks for being a great roommate and a big sister, and thanks for taking good care of me during my pregnancy. Wenjia Wang and Lu Yu, thanks for making my last year at Ann Arbor one to remember. I enjoyed cooking, chatting, karaokeing with you. I also want to say thank you to my old friends from college, Jing Zhao, Liling Wan, Wei Wang, Ziwei Liu, for being my family in the US. Most importantly, I would like to thank my family for their unconditional love, trust and support. I cannot say enough thanks to my Mom and Dad for their help with taking care of Erika. Erika, my little angel, thank you for being healthy and happy. My brother, Chaojie, thank you for taking care of Mom and Dad while I am away. Finally, I want to thank my husband, Yunfei. The 2400 miles between Santa Cruz and Ann Arbor is not easy. Thank you for making all the exhausting trips to visit me. The time with you is always the happiest. I look forward to our family reunion and our new life together! iv TABLE OF CONTENTS DEDICATION .................................................................................................................... ii ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF FIGURES ......................................................................................................... viii LIST OF TABLES ............................................................................................................. ix CHAPTER 1 GENERAL INTRODUCTION .................................................................... 1 1.1 Wnt/β-catenin signaling plays important roles in dorsal axis development in vertebrates ........................................................................................................................... 1 1.1.1 Overview of the Wnt signaling pathway ................................................................ 1 1.1.2 The organizer as signaling center to induce dorsal axis ......................................... 3 Historical perspective .................................................................................................. 3 Molecular nature of the Spemann Organizer ............................................................... 4 Wnt/β-catenin signaling is required for the organizer formation ................................ 5 Organizer genes activated by Wnt/β-catenin signaling ............................................... 7 1.2 TCFs are the major transcription factors of the Wnt/β-catenin pathway ...................... 8 1.2.1 Multiple functions of TCF .................................................................................... 10 DNA binding by TCF ................................................................................................ 10 TCF co-repressors...................................................................................................... 12 TCF co-activators ...................................................................................................... 13 1.2.2 Functional specialization of vertebrate TCF proteins .......................................... 15 1.2.3 TCF transcriptional switch ................................................................................... 19 TCF transcriptional switch in invertebrates............................................................... 19 TCF transcriptional switch in vertebrates .................................................................. 21 1.2.4 Target selection by TCFs ..................................................................................... 22 Insufficiency of TCF binding site .............................................................................. 22 Bipartite binding of some TCF through C-clamp and Helper site interaction .......... 23 Cooperative DNA binding with other transcription factors ...................................... 24 v Genome-wide survey and Transcription Factor collective ........................................ 26 1.3 VegT is a master regulator of mesoendoderm development in Xenopus .................... 27 1.3.1 VegT governs endoderm and mesoderm specification ........................................ 28 1.3.2 VegT is also required for the organizer formation ............................................... 29 1.3.3 T-box proteins in Xenopus ................................................................................... 30 1.3.4 Interaction between T-box proteins and Wnt signaling ....................................... 32 RATIONALE AND SPECIFIC AIMS ............................................................................. 34 CHAPTER 2 INVESTIGATING TARGET SELECTION BY NON-C-CLAMP VERTEBRATE TCFS ...................................................................................................... 45 Abstract ......................................................................................................................... 45 Introduction ................................................................................................................... 46 Results and Discussion .................................................................................................. 49 LEF1 needs a C-clamp to activate Drosophila W-CRMs in Kc cells ....................... 49 LEF1 needs a C-clamp to mediate Wg signaling in developing fly wing ................. 51 Mutagenesis screen uncovers novel cis-regulatory motifs controlling the Wnt responsiveness of the Siamois W-CRM in HEK293T cells ...................................... 53 Materials and Methods .................................................................................................. 57 Acknowledgements ....................................................................................................... 61 CHAPTER 3 VEGT PLAYS A DUAL ROLE IN THE TCF TRANSCRIPTIONAL SWITCH REGULATING SIAMOIS EXPRESSION IN XENOPUS ............................... 75 Abstract ......................................................................................................................... 75 Introduction ................................................................................................................... 76 Results ........................................................................................................................... 79 T-box and TCF sites in the Siamois W-CRM contribute to its repression in ventral blastomeres ................................................................................................................ 79 VegT regulates Siamois transcription by directly binding to the Siamois W-CRM .. 82 HIPK2 disrupts VegT binding to TCF3 .................................................................... 85 VegT also
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