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UNIVERSITY of CALIFORNIA, IRVINE Netrin-Mediated Signaling UNIVERSITY OF CALIFORNIA, IRVINE Netrin-mediated signaling directs central neuron dendrite growth and connectivity in the developing vertebrate visual system DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Anastasia Nicole Nagel Dissertation Committee: Professor Susana Cohen-Cory, Chair Associate Professor Karina S. Cramer Professor Georg F. Striedter 2015 © 2015 Anastasia Nicole Nagel DEDICATION To those who have supported me in my pursuit of understanding the natural world: my husband, family, friends and those who we have lost along the way but who remain present in spirit. “There are naive questions, tedious questions, ill-phrased questions, questions put after inadequate self-criticism. But every question is a cry to understand the world. There is no such thing as a dumb question.” Carl Sagan, The Demon-Haunted World: Science as a Candle in the Dark ii TABLE OF CONTENTS Page LIST OF FIGURES iv ACKNOWLEDGMENTS vi CURRICULUM VITAE vii ABSTRACT OF THE DISSERTATION x INTRODUCTION 1 CHAPTER 1: Molecular signals regulate visual system development 4 Netrin regulates neurodevelopment through diverse receptor binding 9 The role of netrin-1 in retinotectal circuit formation 19 Summary and objectives 27 CHAPTER 2: Netrin directs dendrite growth and connectivity in vivo 29 Introduction 29 Materials and Methods 31 Results 36 Discussion 64 CHAPTER 3: DCC and UNC5 Netrin receptor signaling guides dendritogenesis 70 Introduction 70 Materials and Methods 72 Results 77 Discussion 102 CHAPTER 4: Decreases in Netrin signaling impact visual system function 113 Introduction 113 Materials and Methods 114 Results 116 Discussion 121 CHAPTER 5: Summary and Conclusions 122 REFERENCES 129 iii LIST OF FIGURES Page Figure 1.1 Neuron during general developmental processes 5 Figure 1.2 Signaling molecules that direct visual system formation 8 Figure 1.3 Schematic representation of a netrin-1 gradient in the spinal cord 13 Figure 1.4 Diagram of the X. laevis retinotectal system 21 Figure 1.5 DCC-mediated netrin-1 signaling and RGC axon differentiation 24 Figure 1.6 Netrin-1 has differential effects on axons due to stage 26 Figure 2.1 Expression of Netrin-1 and of its receptors DCC and UNC5 38 Figure 2.2 DCC and UNC-5 expression in the CNS 39 Figure 2.3 Protein diffusion after treatment 41 Figure 2.4 Rapid remodeling of dendritic arbors upon acute manipulations 44 Figure 2.5 Altering netrin levels decreases branch number and total length 45 Figure 2.6 Blocking DCC signaling induces changes in dendritic arbor shape 47 Figure 2.7 Manipulations in netrin levels induce rapid dendrite remodeling 51 Figure 2.8 Altered netrin-1 and DCC signaling impact postsynaptic remodeling 54 Figure 2.9 Postsynaptic cluster addition and stabilization quantification 55 Figure 2.10 Overlays of sample neurons illustrate altered arbor morphology 57 Figure 2.11 Perturbations in netrin signaling alter dendritic arbor directionality 59 Figure 2.12 Individual branches change orientation in response to treatment 60 Figure 2.13 Neuron outcome not affected by altered netrin signaling 63 Figure 3.1 DCC and UNC5 morphant neurons 24h after transfection 79 Figure 3.2 DCC and UNC5 morphant neurons 48h after transfection 80 iv Figure 3.3 DCC and UNC5 morphant neurons 72h after transfection 81 Figure3.4 Receptor down-regulation affects dendrite growth and directionality 85 Figure3.5 Overlays of down-regulated neurons reveal abnormal morphology 86 Figure3.6 Receptor knock down affects filopodia 90 Figure3.7 Down-regulation of DCC and UNC5 induces ectopic basal projections 91 Figure3.8 Altered tectal neuron morphology with receptor down-regulation 93 Figure3.9 Receptor signaling prevents cell division and promotes survival 97 Figure3.10 Netrin receptors influence growth and maturation 98 Figure 3.11 Self-avoidance is not regulated by netrin signaling 101 Figure 4.1 Sequestration of endogenous netrin-1 affects vision 118 Figure 4.2 Total swim time is not affected by altered netrin signaling 120 v ACKNOWLEDGMENTS I would like to express the deepest appreciation to my committee chair, Professor Susana Cohen-Cory, who is the embodiment and provider of patience during my studies at UC Irvine. Her mentorship guided me through difficult times and she always offered genuine support for me during hardships, whether they were difficulties in science or troubles from real life. I have learned so much in the time that we have worked together, and I am grateful for the opportunity to develop myself not only as a scientist but as a well-rounded individual. I thank my committee members, Associate Professor Karina Cramer and Professor Georg Striedter, whose work helped me improve my investigations and direct my research into a cohesive project. Thank you for your advocacy, consideration, and for helping me balance my research and my other duties during my time teaching with you both. In addition I thank the Chair of Neurobiology and Behavior, Professor Marcelo Wood, the man who conducted a challenging albeit invigorating interview with me many years ago. I feel that this interview helped my admission into INP and affirmed my aspirations to be a scientist. Over the years your continued support helping students with teaching and offering encouragement was greatly appreciated by all of us. Thank you for your advocacy. I thank my collaborators: Dr. Sonia Marshak, Dr. Miki Igarashi, Rommel A. Santos, and Sussie Gill; those who have helped me with my research as technical support: Lilly Zuniga and Sarah D. Mortero; and my 199 or volunteer students: Rommel A. Santos, Marc Piercy, Anthony Gallegos, Solomon Tang, Nathan Cruz, Gail Suchoknand, Arsany Bechay , Leslie Ocampo, Bryan Carbaugh, Myrna Leal, Tydus Thai, Mamdouh Hanna, Jimmy Villa, Rozhin Eskandary, Sabrina Lebron, Ruthy Mamo. Lastly, I thank Professor Oswald Steward, Dr. David Kinker, and Professor Clark Lindgren, all of whom helped me get to graduate school. I would also like to thank my family. I give a special thanks to my uncle, Dr. Robert Kunkle, for telling me his dissertation story so that I would be inspired during difficult times. I thank John Nagel for his proofreading and emotional support, and I especially thank Dr. Brian Marion, my husband who has helped me with my research and with generally being whole and sane during this process. Financial support was provided by the National Eye Institute grant EY-011912 to Susana Cohen-Cory and a Department of Education GAANN award P200A120165 to Professor Karina Cramer. vi CURRICULUM VITAE Anastasia Nicole Nagel 2005 B.A. with Honors in Biology, Grinnell College, Grinnell, IA 2006 Research Technician, Department of Genetics, Duke University, Durham, NC 2007-2009 Research Assistant, Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA 2009-2015 Graduate Student Researcher, Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 2011-2014 Teaching Assistant, Ayala School of Biological Sciences, University of California, Irvine, Irvine, CA 2014 Teaching Assistant for Graduate Student Cellular Neuroscience Lab Course, Ayala School of Biological Sciences, University of California, Irvine, Irvine, CA 2015 Ph.D. in Neurobiology and Behavior, Ayala School of Biological Sciences, University of California, Irvine FIELD OF STUDY Neurobiology of central nervous system wiring during development PUBLICATIONS Marion B*; Mclean K*; and Nagel A*. 2005. Blocking of muscarinic receptors does not affect post tetanic response in frog neuromuscular junction. Pioneering Neuroscience, 6, 5-8. *indicates shared first co-authorship Nagel AN*, Marshak S*, Manitt C, Santos RA, Piercy MA, Mortero, SD, Shirkey-Son, NJ, and Cohen-Cory S. “Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo.” Neural Development (in press) 2015. *indicates shared first co- authorship CONFERENCE PRESENTATIONS 2011 Marshak S*, Nagel A*, Manitt C, and Cohen-Cory S. Netrin influences the directionality of dendritic arbor growth and postsynaptic connectivity in the vii developing Xenopus visual system. 2011 Abstract. Washington, DC: Society for Neuroscience, 2011. Online. 2013 Nagel A*, Marshak S*, Santos RA, Hung V, and Cohen-Cory S. DCC-mediated netrin-1 signaling influences dendritic arbor orientation and growth dynamics in the developing Xenopus visual system. 2013 Abstract and Poster. San Diego, CA: Society for Neuroscience, 2013. PROFESSIONAL MEMBERSHIPS, SCHOLARSHIPS, AND AWARDS 2012 HHMI Graduate Fellow Award for Teaching 2012 Belegarth Scholarship Award (Academic Performance & Community Service in BMCS) 2012-2014 GAANN Fellowship 2010- 2015 Society for Neuroscience Member TEACHING AND MENTORSHIP 2011 Spring Instructor Neurobiology Lab 2011 Spring Teaching Assistant Neurobiology and Behavior 2011 Fall Teaching Assistant/ Substitute Neural Development 2012 Winter Instructor Neurobiology Lab 2012 Spring Teaching Assistant Functional Neuroanatomy 2012 Summer Session I Introductory Biology 2012 Summer Session II Introductory Biology (Online Course) 2012 Fall Introductory Biology 2013 Winter Teaching Assistant Functional Neuroanatomy 2014 Winter Teaching Assistant Cellular Neuroscience Graduate Level Lab 2010 – Present Mentored 11 undergraduate students in Undergraduate Research Opportunities Program (UROP), Excellence in Research, and BRIDGES. All of the students I mentored in Excellence in Research received this award and published in the Journal of Undergraduate Research
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