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Δ-Protocadherin Function: from Molecular Adhesion Properties to Brain Circuitry

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Δ-Protocadherin Function: from Molecular Adhesion Properties to Brain Circuitry δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Sharon Rose Cooper Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2017 Dissertation Committee: Dr. James Jontes, Advisor Dr. Marcos Sotomayor, Co-advisor Dr. Heithem El-Hodiri Dr. Sharon Amacher Copyrighted by Sharon Rose Cooper 2017 Abstract Selective cell-to-cell adhesion is essential for normal development of the vertebrate brain, contributing to coordinated cell movements, regional partitioning and synapse formation. Members of the cadherin superfamily mediate calcium-dependent cell adhesion, and selective adhesion by various family members is thought to contribute to the development of neural circuitry. Members of the δ-protocadherin subfamily of cadherins are differentially expressed in the vertebrate nervous system and have been implicated in a range of neurodevelopmental disorders: schizophrenia, mental retardation, and epilepsy. However, little is known about how the δ- protocadherins contribute to the development of the nervous system, nor how this development is disrupted in the disease state. Here I focus on one member of the δ-protocadherin family, protocadherin-19 (pcdh19), since it has the clearest link to a neurodevelopmental disease, being the second most clinically relevant gene in epilepsy. Using pcdh19 transgenic zebrafish, we observed columnar modules of pcdh19-expresing cells in the optic tectum. In the absence of Pcdh19, the columnar organization is disrupted and visually guided behaviors are impaired. Furthermore, similar columns were observed in pcdh1a transgenic zebrafish, located both in the tectum and in other brain regions. This suggests protocadherin defined columns may be a theme of neural development. ii Our X-ray crystal structure of Pcdh19 reveals the adhesion interface for Pcdh19 and infers the molecular consequences of epilepsy causing mutations. We found several epilepsy causing mutations were located at the interface and disrupted adhesion, which further validated the interface and revealed a possible biochemical cause of Pcdh19 dysfunction. Furthermore, sequence alignments of other δ-protocadherins with Pcdh19 suggest that this interface may be relevant to the entire δ-protocadherin subfamily. We used the information gained about Pcdh19 to design PCDH19-FE mutations in the genome of zebrafish for comparing the circuitry of embryos with wild-type pcdh19, non-adhesive pcdh19 or without pcdh19. The combination of in vitro adhesion studies and in vivo brain imaging analysis provides a more comprehensive understanding of protocadherin-19 function, and suggests a broader role for the δ- protocadherin family in differential adhesion during brain development. iii This work is dedicated to my family for their unconditional love and support. iv Acknowledgments First, I would like to thank both of my advisors, Dr. James Jontes and Dr. Marcos Sotomayor, for their mentorship. I appreciate their sincere investment in my research projects and my development as a scientist. I am also thankful to my committee members for their guidance. Thank you to all the members of the Jontes and Sotomayor labs for their comradery and scientific insights. A special thank you goes to Dr. Michelle Emond, who has taught me many valuable research techniques. I would also like to thank Deepanshu Choudhary and Avinash Jaiganesh for their advice on differential scanning fluorimetry, and Dr. Raul Araya-Secchi for his assistance with structural biology software. Additionally, I would like to thank our collaborator, Marc Wolman, for performing behavioral analysis on the pcdh19 mutant zebrafish. I am also grateful for technical assistance and advice from Dr. Min An, Dr. Jared Talbot, Dr. Michael Berberoglu, Dr. Hao Le, and Phan Duy. I would like to acknowledge the Jeffery J. Seilhamer Cancer foundation for its financial support during my final years of graduate school. Thank you for the honor and privilege of being a Seilhamer fellow. Last but not least, I would like to thank my family for their constant encouragement, particularly my husband for his understanding and support through the ups-and downs of pursuing my doctorate. v Vita 2009 ...............................................................Research Intern, University of Arkansas for Medical Sciences 2010 ...............................................................Research Intern, Princeton University 2010 ...............................................................B.S. Molecular and Cellular Biology, Cedarville University 2011 to present .............................................Graduate Research Associate, Department of Neuroscience, and Department of Chemistry and Biochemistry, The Ohio State University Publications 1. Cooper, S. R., Emond, M. R., Duy, P. Q., Liebau, B. G., Wolman, M. A., & Jontes, J. D. (2015). Protocadherins control the modular assembly of neuronal columns in the zebrafish optic tectum. The Journal of Cell Biology, 211(4), 807–814. http://doi.org/10.1083/jcb.201507108 2. Cooper, S. R., Jontes, J. D., & Sotomayor, M. (2016). Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy. eLife, 5. http://doi.org/10.7554/eLife.18529 Fields of Study Major Field: Molecular, Cellular and Developmental Biology vi Table of Contents Abstract ................................................................................................................................ii Acknowledgments................................................................................................................ v Vita ...................................................................................................................................... vi List of Tables ........................................................................................................................ x List of Figures ...................................................................................................................... xi Chapter 1: Introduction ...................................................................................................... 1 The Cadherin Superfamily and Adhesion .............................................................. 3 Neural Circuitry, Neurodevelopmental Disease, and the δ-Protocadherins ...... 19 Pcdh19 Female Epilepsy ...................................................................................... 25 Zebrafish as a Neurodevelopmental Model ........................................................ 30 Multidisciplinary Approach to a Fundamental Question .................................... 34 Chapter 2: Protocadherins Control the Modular Assembly of Neuronal Columns in the Zebrafish Optic Tectum ..................................................................................................... 40 Abstract ............................................................................................................... 40 Introduction ......................................................................................................... 41 Results and Discussion ........................................................................................ 42 Materials and Methods ....................................................................................... 48 vii Chapter 3: Structural Determinants of Adhesion by Protocadherin-19 and Implications for its Role in Epilepsy ....................................................................................................... 65 Abstract ................................................................................................................ 65 Introduction ......................................................................................................... 66 Results ................................................................................................................. 69 Discussion and Conclusions ................................................................................. 83 Materials and Methods ....................................................................................... 87 Chapter 4: Creating PCDH19 Female Epilepsy Mutations in the Endogenous Zebrafish pcdh19 Gene by CRISPR Genome Editing ....................................................................... 115 Introduction ....................................................................................................... 115 Results ............................................................................................................... 117 Conclusions and Future Directions .................................................................... 119 Materials and Methods ..................................................................................... 120 Chapter 5: Anatomy of Protocadherin1a Expressing Cells Reveals a Theme of Columnar Development in the Zebrafish Brain ............................................................................... 129 Introduction ....................................................................................................... 129 Results ............................................................................................................... 130 Discussion .......................................................................................................... 134 Material and methods ......................................................................................
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