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Cellular Mechanisms That Promote the Collective

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Cellular Mechanisms That Promote the Collective CELLULAR MECHANISMS THAT PROMOTE THE COLLECTIVE MIGRATORY BEHAVIOR OF DROSOPHILA BORDER CELLS by GEORGE GIL F. ARANJUEZ Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Genetics and Genome Sciences CASE WESTERN RESERVE UNIVERSITY August, 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of George Gil F. Aranjuez candidate for the degree of Doctor of Philosophy. Committee Chair Dr. Helen Salz Committee Member / Mentor Dr. Jocelyn McDonald Committee Member Dr. Heather Broihier Committee Member Dr. Hua Lou Date of Defense July 7, 2015 *We also certify that written approval has been obtained for any proprietary material contained therein. 2 TABLE OF CONTENTS LIST OF TABLES ............................................................................................................ 7 LIST OF FIGURES .......................................................................................................... 8 ACKNOWLEDGEMENTS ........................................................................................... 11 ABSTRACT ..................................................................................................................... 13 CHAPTER 1. INTRODUCTION .................................................................................. 15 COLLECTIVE MIGRATION DURING NORMAL DEVELOPMENT ............. 16 Collective movement of two-dimensional cell sheets .............................. 16 Sprouting and branching involves leading tip cells that pull the cells behind to form new structures ........................................................... 18 Freely-migrating collectives ..................................................................... 19 COLLECTIVE CELL MIGRATION IN CANCER ............................................. 21 Maintenance of cell-cell adhesions ........................................................... 22 Response to growth factors ....................................................................... 22 Remodeling and responding to the environment ...................................... 23 HALLMARKS OF COLLECTIVE MIGRATION .............................................. 24 Control of protrusion formation and directionality ................................... 24 Constant cell-cell interaction .................................................................... 25 Migration of border cells occur in a ligand-guided fashion ...................... 29 Precise control of border cell protrusions is essential for efficient cluster migration ............................................................................................ 30 3 OUTSTANDING QUESTIONS PERTAINING TO COLLECTIVE BORDER CELL MIGRATION ..................................................................................... 32 CHAPTER 2. ON THE ROLE OF PDZ DOMAIN-ENCODING GENES IN DROSOPHILA BORDER CELL MIGRATION ................................................. 42 INTRODUCTION ................................................................................................ 43 RESULTS ............................................................................................................. 46 RNAi knockdown of PDZ domain-encoding genes in border cells ......... 46 Validation of candidates ........................................................................... 50 Investigation of two genes, bbg and CG6509, reveals distinct functions in border cells ......................................................................................... 53 DISCUSSION ....................................................................................................... 57 RNAi knockdown of specific classes of genes to identify regulators of border cell migration .......................................................................... 57 Epithelial polarity and cytoskeletal-associated genes are highly represented hits .................................................................................. 60 Roles of Bbg and CG6509 in cell migration ............................................. 63 MATERIALS AND METHODS .......................................................................... 64 Drosophila Genetics ................................................................................. 64 In vivo RNAi Knockdown ........................................................................ 65 Quantitative RT-PCR Analysis of Gene Expression ................................ 66 Immunostaining and Microscopy ............................................................. 67 Calculation of Stat92E/DAPI Intensity Ratio ........................................... 68 Graphs, Statistics, and Figures .................................................................. 69 4 CHAPTER 3. DOP KINASE IS REQUIRED FOR STEREOTYPIC PROTRUSION FORMATION IN COLLECTIVELY MIGRATING BORDER CELL CLUSTERS IN DROSOPHILA ........................................................................... 100 INTRODUCTION .............................................................................................. 101 RESULTS AND DISCUSSION ......................................................................... 104 Loss of dop in border cells results in failure to complete migration ...... 104 Loss of dop does not affect border cell position in the cluster ............... 107 Loss of dop results in multiple protrusions ............................................. 108 Dop mutant clusters extend misshapen protrusions ................................ 110 Loss of dop does not alter the levels of F-actin or microtubules in border cells .................................................................................................. 110 Altering microtubule dynamics does not rescue the migration defects due to dop RNAi ..................................................................................... 111 CONCLUSION AND FUTURE DIRECTIONS ................................................ 112 MATERIALS AND METHODS ........................................................................ 114 Drosophila genetics ................................................................................ 114 Immunostaining and imaging ................................................................. 115 Figures, Graphs, and Statistics ................................................................ 115 CHAPTER 4. COLLECTIVE CELL SHAPE REQUIRES MYOSIN ACTIVITY AT THE GROUP PERIPHERY DURING IN VIVO MIGRATION ............... 130 INTRODUCTION .............................................................................................. 131 RESULTS AND DISCUSSION ......................................................................... 133 5 Myo-II is required for border cells to maintain cluster shape during migration .......................................................................................... 133 Activated Myo-II is localized to the cluster periphery and promotes cell and cluster shape .............................................................................. 135 Maintenance of cluster shape requires dynamic Myo-II ......................... 138 Nurse cell confinement influences border cell cluster shape and migration ......................................................................................................... 141 MATERIALS AND METHODS ........................................................................ 143 Drosophila strains and genetics .............................................................. 143 Immunostaining and imaging ................................................................. 145 RT-PCR .................................................................................................. 146 Image Analyses, Figures, Graphs and Statistics ..................................... 146 CHAPTER 5. FINAL DISCUSSION .......................................................................... 165 Continue to develop experimental models of collective migration ........ 165 Strategies for identifying new components of collective migration mechanisms ...................................................................................... 168 Studying the interplay between collective migration and the environment ......................................................................................................... 170 Cortical tension at the collective level .................................................... 171 BIBLIOGRAPHY ......................................................................................................... 176 6 LIST OF TABLES TABLE 2-1. High confidence PDZ domain-encoding genes in border cell migration identified by RNAi knockdown ................................................................................. 82 TABLE 2-2. Expression Levels and RNAi Knockdown Efficiency as Measured by Quantitative RT-PCR ................................................................................................. 84 Table 2-S1. Complete results of the PDZ RNAi survey of border cell migration ............ 86 7 LIST OF FIGURES Figure 1-1. Examples of collective migration in normal development ............................ 34 Figure 1-2. Border cell migration occurs during mid-oogenesis ...................................... 36 Figure 1-3. Strict regulation of protrusion formation is the key to efficient migration of the border cell cluster ................................................................................................. 38 Figure 1-4. Components of
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