Using Drosophila oogenesis to define the role of prostaglandin signaling in collective invasive cell migration
Year: 2019
Type: dissertation
Abstract: Collective cell migration is the movement of groups of cells in a coordinated and connected manner. It is essential in development, and has recently been connected to the spread of cancer metastasis. Despite the fact that collective cell migration is essential, most studies of cell migration are looking at single cell migration events. While many of the same processes that regulate single cell migration likely regulate collective cell migration, collective cell migration presents its own individual challenges. For this reason, it is important to study genes and signaling molecules known to regulate single cell migration in the collective cell context. One regulator of single cell migration that has not been looked at in the context of collective cell migration is Prostaglandin Signaling. Prostaglandins are short range, lipid signaling molecules regulated by release of arachidonic acid and by the conversion of that arachidonic acid into the prostaglandin precursor by cyclooxygenases. There are two cyclooxygenase enzymes in humans (COX1 and COX2), and these enzymes are the targets of many non-steroidal anti-inflammatory drugs like aspirin. Studies in both mice, zebrafish, and humans all show that these enzymes are essential to development and can regulate cancer cell metastasis. This thesis focuses on prostaglandins in collective cell migration, and how they regulate this process. Using Drosophila melanogaster oogenesis, we examine the role of the Drosophila Cox like enzyme Pxt in border cell migration. Border cell migration occurs during Stage 9 of oogenesis and consists of a set of 8-10 somatic cells which delaminate from the anterior tip of the follicle and migrate collectively between the much larger nurse cells to the nurse cell-oocyte border. This migration is essential to the fertility of the female fly, and is a common model for examining collective cell migration. Here I make use of this model to examine the effects of pxt both within the migratory cells, and within the nurse cells which represent the microenvironment of the border cell cluster. To do this however, I first had to develop a new method of migration quantification. Chapter 2 outlines the method I developed to quantify border cell migration using fixed imaging analysis. Typically border cell migration is assessed at Stage 10 to look for completion, or during Stage 9 using live imaging. As live imaging proved impossible in these mutants, I assessed border cell migration using a fixed imaging analysis that quantifies the amount the border cell cluster is ahead of or behind the position of the outer follicle cells. As the outer follicle cell position is not altered in any known border cell mutants, we are able to take advantage of this fact to assess border cell migration in a highly quantitative method. In Chapter 3, I present the main body of my thesis and show that Pxt is essential to proper border cell migration. Here I show that loss of pxt results in delayed border cell migration and apparent cluster morphology defects. I also show that somatic loss of Pxt results in delayed migration but without apparent cluster morphology defects. From the results presented in this chapter I propose that border cell migration is regulated both within the migratory cells, and by the microenvironment of these cells. In conclusion, prostaglandins are essential in collective, invasive cell migration and act both within the migratory cluster and in the surrounding microenvironment in different ways to promote migration. These functions, which are likely conserved across species, are essential to proper migration and make excellent targets for better understanding of their role in development and in disease. It is likely that the work presented in this thesis lays the groundwork for future experiments which will better understand the targets of prostaglandin signaling in both the microenvironment and the migratory cells. Furthermore, it further establishes Drosophila as an excellent model for understanding the mechanisms behind prostaglandin signaling.
DOI: 10.17077/etd.005256
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4246381927