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Regulation of Axon Guidance Receptor Expression and Activity During Neuronal Morphogenesis University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Regulation Of Axon Guidance Receptor Expression And Activity During Neuronal Morphogenesis Celine Santiago University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Developmental Biology Commons, Genetics Commons, and the Neuroscience and Neurobiology Commons Recommended Citation Santiago, Celine, "Regulation Of Axon Guidance Receptor Expression And Activity During Neuronal Morphogenesis" (2016). Publicly Accessible Penn Dissertations. 2568. https://repository.upenn.edu/edissertations/2568 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2568 For more information, please contact [email protected]. Regulation Of Axon Guidance Receptor Expression And Activity During Neuronal Morphogenesis Abstract Receptors expressed on the surface of neurons during development direct cell migration, axon guidance, dendrite morphogenesis, and synapse formation by responding to cues in the neuron’s environment. The expression levels and the activity of cell surface receptors must be tightly controlled for a neuron to acquire its unique identity. Transcriptional mechanisms are essential in this process, and many studies have identified requirements for specific transcription factors during the different steps of neural circuit assembly. However, the downstream effectors by which most of these factors control morphology and connectivity remain unknown. In Chapter 1, I highlight recent work that elucidated functional relationships between transcription factors and the cellular effectors through which they regulate neural morphogenesis and synaptogenesis in multiple model systems. In Chapters 2 and 3, I present data demonstrating that the homeodomain transcription factors Hb9 and Islet control motor axon guidance in Drosophila embryos through distinct effectors: Hb9 regulates the (Roundabout) 2 receptor in a subset of motor neurons, while Islet acts in the same cells to regulate the Frazzled/DCC receptor. Genetic rescue experiments indicate that these relationships are functionally important for the guidance of motor axons to their muscle targets. In addition, Islet regulates motor neuron dendrite targeting in the central nervous system (CNS) through Frazzled, demonstrating how an individual transcription factor can control multiple aspects of neuronal connectivity through the same effector. In Chapter 4, I characterize a non-canonical function for the Robo2 receptor during midline crossing, and present data suggesting that this activity requires Robo2 to be expressed in midline cells, providing an example of how mechanisms that regulate guidance receptor gene expression are key to regulating receptor function and nervous system formation. In Chapter 5, I explore the implications of these findings, and propose future directions of research to build upon them. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Greg J. Bashaw Keywords Axon guidance, Frazzled, Homeodomain proteins, Motor neurons, Roundabout Subject Categories Developmental Biology | Genetics | Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2568 REGULATION OF AXON GUIDANCE RECEPTOR EXPRESSION AND ACTIVITY DURING NEURONAL MORPHOGENESIS Celine Santiago A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation ___________________________________ Greg J. Bashaw, Professor of Neuroscience Graduate Group Chairperson _______________________ Daniel Kessler, Associate Professor of Cell and Developmental Biology Dissertation Committee: Stephen DiNardo, Professor of Cell and Developmental Biology Wenqin Luo, Assistant Professor of Neuroscience Jonathan Raper, Professor of Neuroscience Meera Sundaram, Associate Professor of Genetics ACKNOWLEDGMENTS I would like to thank the members of the Bashaw lab for their mentorship, support, and friendship throughout the years. In particular, I thank Greg for having created a stimulating research environment where curiosity and critical thinking are always encouraged. Our many conversations over the years helped me communicate more clearly and think more deeply about science, and were a major part of my growth and of the joy of working in the lab. I am also very grateful for all his encouragement, which gave me the confidence to get past disappointments, and to push myself to try new things, and for his relentless advocacy and support for me as I prepare to move on to the next stage of my career. I thank Alexandra and Mike for having been such great mentors and friends. I am a better scientist for having worked by their side, and they continue to inspire me to be more ambitious and thoughtful. A special thank you to Alexandra for her wisdom and thoughtful words every time I needed advice. Thanks to Melissa for having shared all the milestones of graduate school with me, from the early days of our rotation to proof- reading each other’s papers. I thank Tim and Elise for a productive collaboration on the Robo2 pro-crossing project, and all the other members of the Bashaw lab for having made it such a fun place to work. I would also like to thank the members of my thesis committee for their advice and mentorship, both about experiments and about my career. I am also grateful for the guidance of mentors from before grad school: Daniel Wagner, for a wonderful ii undergraduate research experience that led me down this path; and Robert Dennison and Deborah Crawford, for sharing their passion and curiosity about the natural world with their students. Last but not least I would like to thank all of my other friends and family, especially Julie, for having been by my side through all the adventures of the past six years, and Michael, for his unwavering support and sense of humor. I thank my brother and my sister in law for their friendship and advice, especially during interviews in the past year. Finally, I thank my parents, to whom I dedicate this thesis. They did everything they could to help me and my brother find our paths, and their perseverance and courage in difficult moments throughout their own lives showed me how important it is to always keep trying. iii ABSTRACT REGULATION OF AXON GUIDANCE RECEPTOR EXPRESSION AND ACTIVITY DURING NEURONAL MORPHOGENESIS Celine Santiago Greg J. Bashaw Receptors expressed on the surface of neurons during development direct cell migration, axon guidance, dendrite morphogenesis, and synapse formation by responding to cues in the neuron’s environment. The expression levels and the activity of cell surface receptors must be tightly controlled for a neuron to acquire its unique identity. Transcriptional mechanisms are essential in this process, and many studies have identified requirements for specific transcription factors during the different steps of neural circuit assembly. However, the downstream effectors by which most of these factors control morphology and connectivity remain unknown. In Chapter 1, I highlight recent work that elucidated functional relationships between transcription factors and the cellular effectors through which they regulate neural morphogenesis and synaptogenesis in multiple model systems. In Chapters 2 and 3, I present data demonstrating that the homeodomain transcription factors Hb9 and Islet control motor axon guidance in Drosophila embryos through distinct effectors: Hb9 regulates the (Roundabout) 2 receptor in a subset of motor neurons, while Islet acts in the same cells to regulate the Frazzled/DCC receptor. Genetic rescue experiments indicate that these relationships are functionally important for the guidance of motor axons to their muscle targets. In iv addition, Islet regulates motor neuron dendrite targeting in the central nervous system (CNS) through Frazzled, demonstrating how an individual transcription factor can control multiple aspects of neuronal connectivity through the same effector. In Chapter 4, I characterize a non-canonical function for the Robo2 receptor during midline crossing, and present data suggesting that this activity requires Robo2 to be expressed in midline cells, providing an example of how mechanisms that regulate guidance receptor gene expression are key to regulating receptor function and nervous system formation. In Chapter 5, I explore the implications of these findings, and propose future directions of research to build upon them. v TABLE OF CONTENTS ACKNOWLEDGMENTS ............................................................................................... II ABSTRACT ..................................................................................................................... IV LIST OF ILLUSTRATIONS ......................................................................................... IX PREFACE ...................................................................................................................... XII CHAPTER 1 ...................................................................................................................... 1 INTRODUCTION: TRANSCRIPTION FACTORS AND EFFECTORS THAT REGULATE AXON GUIDANCE, DENDRITE MORPHOLOGY, AND SYNAPTOGENESIS IN THE DEVELOPING NERVOUS SYSTEM ......................
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