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Interrogating the Development of Enteric Nervous System in Zebrafish Using Transcriptomics Sweta Roy-Carson Iowa State University

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Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2019 Interrogating the development of Enteric Nervous System in zebrafish using transcriptomics Sweta Roy-Carson Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Bioinformatics Commons Recommended Citation Roy-Carson, Sweta, "Interrogating the development of Enteric Nervous System in zebrafish using transcriptomics" (2019). Graduate Theses and Dissertations. 17303. https://lib.dr.iastate.edu/etd/17303 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Interrogating the development of Enteric Nervous System in zebrafish using transcriptomics by Sweta Roy-Carson A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Bioinformatics and Computational Biology Program of Study Committee: Drena Dobbs, Co-major Professor Matthew Hufford, Co-major Professor Carolyn Dill Donald Sakaguchi Heike Hofmann The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2019 Copyright © Sweta Roy-Carson, 2019. All rights reserved. ii DEDICATION This thesis is dedicated to my grandfather Dr. Binoy Kumar Singh Roy for paving a way for this family to get education and follow their dreams. I know you wanted to see all of us succeed and reach the zenith of education dadu and you would have been very proud of your didi today! iii TABLE OF CONTENTS Page ACKNOWLEDGMENTS v ABSTRACT vii CHAPTER 1. INTRODUCTION 8 Enteric Nervous System 8 Subtypes of Enteric Neurons 17 Evolutionary conservation of ENS 22 Zebrafish as a Model Organism 24 Organization of the Thesis 25 References 26 Figures 37 Tables 39 CHAPTER 2. DEFINING THE TRANSCRIPTOMIC LANDSCAPE OF THE DEVELOPING ENTERIC NERVOUS SYSTEM AND ITS CELLULAR ENVIRONMENT 40 Abstract 40 Background 40 Materials and Methods 45 Results 49 Discussion 61 Conclusion 75 List of abbreviations 75 Ethics approval 75 Acknowledgement 76 References 76 Figures 90 Tables 99 iv CHAPTER 3. DISCOVERING DEVELOPMENTAL DYNAMICS OF ENTERIC NEURONS: ONE CELL AT A TIME 106 Abstract 106 Introduction 107 Materials and Methods 110 Results 115 Discussion 131 References 136 Figures 142 Tables 149 CHAPTER 4. GENERAL CONCLUSION 151 Introduction 151 Lineage-specific Transcription Profile of the Intestinal Cells 152 Subpopulation of Enteric Neurons Exist Throughout Development 154 Future Directions 156 Significance of the Dissertation 157 References 158 v ACKNOWLEDGMENTS I would like to start by thanking my guide and mentor, Dr. Julie Kuhlman who has taught me all about enteric nervous system. My major professor and the chair of my committee, Dr. Drena Dobbs, my co-major professor, Dr. Matthew Hufford, and my committee members, Dr. Carolyn Dill, Dr. Donald Sakaguchi and Dr. Heiki Hofmann, for their guidance and support throughout the course of this research. A special thanks to Dr. Hufford for his invaluable suggestions, advice and support in the past year. I would also like to extend a special thank you to Dr. Carolyn Dill, for providing me with a lab space and a ‘foster’ lab family. Apart from my committee I would also like to thank Dr. Stephan Schneider, who played an integral part in the initial phase of my PhD and Trish Stauble who has helped me in every step of the PhD journey starting even before I entered this country. I would like to thank my parents, Dr. Nikhil Kumar Roy and Mrs. Archana Roy, for their constant encouragement and support during not only my PhD but my whole life. They have made sacrifices that cannot be described in words. They have always put our needs and wants before their own and made sure that I achieved every goal in my life. My grandmother, Mrs. Lekha Roy, who has always shown me what it is to be a strong independent woman and been my go-to person for the times when I felt I had hit a dead-end. My little brother, Jyotirmoy Roy, was the one who showed me dreams and also had faith in me, that helped me move forward and trust myself. I want to thank my whole family who showed me the importance of education and filling my life with love, trust, learning and happiness which were such big ingredients in making me the person that I am today. I also want to thank my mother-in-law, Pamela Hundley, sister-in-law, Emily Carson and brother-in-law, Justin Stoll for being kind and caring and being my rock to fall back on in this country. vi I have been blessed with the best people as friends and I wanted to name each one of them because they played a very important part during my PhD. Ankita, Sabiha and Prerna, we started our masters together and we are still each other’s support. Vivek, Dharmin and Bhagyashree have been there to listen to and lessen my PhD life woes. We have shared laughter and tears together and I am grateful for you guys in my life. It’s hard to put into words how much you guys have helped me, especially Vivek who has shown me what resilience and patience means. You are an inspiration to so many and I thank the three of you for being my support and having faith in me. I want to thank Maitry for being my soul sister and listening to my silly complaints and making delicious food to always cheer me up. My lab family Kendra, Kevin and Natalia, who apart from listening to my everyday lab woes also helped me to move in the right direction. Jennifer Chang, Kannan Sankar and Gokul, who have been with me since my first year at the university and have literally taught me bioinformatics. And my friends who became my family, Divita, Nikhil, Pooja, Archit, Rahul and Amber. You have been my guide, my go-to people for the most miniscule to the most gigantic problems, my support and my inspirations. Thank you for being my people. A special shout out to Freya Roy (Rahul and Amber’s progeny), our goddaughter for being my little stress buster and filling my life with so much joy and happiness. Last but not the least I would like to give the biggest and most heartfelt thank you to my husband Joshua Carson. I wouldn’t have been able to graduate without your help. We have been through so much together especially because of the graduate school experience and we did it! You have motivated, encouraged, loved and trusted me. You have helped me solve all my problems, research or personal, and cleaning up all my messes. Thank you for helping me overcome my fears and having faith in me more than I did in myself. This degree is not just mine; it is ours. vii ABSTRACT The enteric nervous system (ENS) is the set of neurons that control the activity of the gastrointestinal system. These activities include secretion of digestive juices, absorption of food, and motility of the gut. The enteric neurons are derived from the neural crest cells (NCC) which migrate to the gut during development. We have a sparse knowledge of the genes and the signaling pathways that are known to be involved in the migration, specification, and differentiation of the enteric neurons from neural crest precursors. Malfunction in any of these processes hampers normal ENS development and can result in a variety of diseases including Hirschsprung’s disease, a disorder in which the distal intestinal tract lacks enteric neurons. With the aid of transcriptomic study, we aimed to understand the molecular basis behind the different processes of development of a functional enteric nervous system using zebrafish as our model organism. In my research, we were able to generate the transcriptome of the neuronal cells as well as of the microenvironment that is known to provide external signals to these neurons in a normal developing ENS. We were able to identify previously linked genes and pathways associated with ENS development and also ascertain a large number of novel candidate genes that might be potential regulators in driving a normal ENS development. We also tried to elucidate the heterogeneity that exists between enteric neurons by performing a single cell transcriptomic study. Our findings from this project provided an insight into the different genetic and molecular factors that are specific to the different developmental stages. Along with shedding a light on the developmental timeline, this project also assisted in unraveling the factors distinctive of the subpopulations of the enteric neurons that reside in the gastrointestinal tract. 8 CHAPTER 1. INTRODUCTION Enteric Nervous System The digestive system is responsible for nutrition absorption as well as removal of waste from our system. It is not so well-known that these processes are actually controlled by the complex network of neurons and glia, called the enteric nervous system (ENS), that reside in the gastrointestinal tract. The ENS, also known as the “second brain” in popular culture, forms the biggest part of the peripheral nervous system (PNS) and is capable of functioning without any input from the central nervous system (CNS). In mammals, the enteric neurons and glia are arranged into ganglia, and consists of phenotypically varied cells.
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