Defining the cell-specific roles of two prostaglandins in Drosophila border cell migration
Creators: name: Mellentine, Samuel Q.
Publisher: name: University of Iowa
Year: 2023
Subjects: Border cells
cell migration
Drosophila
PGE2
PGF2α
Prostaglandins

description: Cell migration drives many biological processes. Cell migration exists in two forms: single cell migration in which a single cell moves towards a specific site and collective cell migration in which a group or cluster of cells move together following a specific signal. There are examples of both throughout biology. Cell migration can be beneficial, such as during development and wound healing, or be detrimental, such as cancer metastasis. Many processes contribute to cell migration. Processes from within the migrating cell(s) can propel migration, such as the creation of protrusions, restructuring of cellular architecture and communication with the microenvironment. Factors can also originate from the microenvironment to influence migration. These factors include signals that drive migration and the stiffness of the microenvironment. My project focuses on uncovering the mechanisms regulating collective cell migration.
description: Collective migration is regulated by many signaling pathways, one class of which is prostaglandin (PG) signaling. PGs are short-range lipid signaling molecules. The synthesis of PGs begins with the conversion of arachidonic acid to a PG precursor by a cyclooxygenase (COX) enzyme. The PG precursor is acted on by specific synthases to become one of several PGs. These bio-active PGs then signal in either an autocrine or paracrine manner through G-protein coupled receptors to begin signaling cascades. How PG signals that originate from the migratory cells versus how PG signals from the microenvironment (or the substrate) regulate collective cell migration remains largely unknown.
description: PG signaling promotes many developmental collective cell migrations. However, these experiments perturbed PG signaling throughout the whole organism. Thus, these studies were unable to identify the cellular source of PG and where it signals to. PG signaling also promotes cancer metastasis. Many of these studies are performed using in vitro 2-D cell culture models which do not allow for the analysis of the roles of PGs from the substrate on the migratory cells. To uncover the roles of PGs from within the migratory cells as well as the substrate we use the collective migration of the border cells during Drosophila oogenesis as our model.
description: Border cell migration is a well-studied and widely used model of an invasive, collective cell migration. At the beginning of Stage 9 of oogenesis, the border cells are specified from the follicle cells by the two anterior polar cells. The border cells form a cluster and detach from the anterior end and move posteriorly between their nurse cell substrate until they reach the developing oocyte. This migration is critical for fertility, as border cells aid in the development of the micropyle. Prior research in the lab established PG signal is required for on-time migration and maintaining cluster morphology. Loss of the Drosophila COX-like enzyme, Pxt results in delayed migration and elongated clusters. For clarity, Pxt will subsequently be referred to as dCOX1. Key questions from the prior studies are which PGs promote border cell migration, where are these PGs produced – from the migratory cells or from the substrate, and what are the downstream mechanisms whereby these PGs act.
description: In Chapter 2, I present data revealing that two PGs, PGE2 and PGF2α, are required for on-time border cell migration. Specifically, PGE2 is produced by the cytoplasmic PGE2 synthase (cPGES) within the substrate to promote on-time migration. Whereas, PGF2α is produced by its synthase, Akr1B, in the border cells to drive migration. Further, PGF2α has cell-specific roles in regulating cluster morphology. Reduction of Akr1B within the border cells results in smaller, more compact clusters, whereas reduction in the substrate results in cluster elongation. Finally, I uncover potential mechanisms by which these PGs may regulate border cell migration including integrin localization and Myosin activity. The localization of integrin-based adhesions on the border cell membranes requires PGF2α but not PGE2 production. Further, both PGF2α and PGE2 regulate cellular stiffness. Limiting Myosin activity to the appropriate level on the border cell cluster requires both PGF2α and PGE2 production, however, limiting Myosin activity in the substrate requires PGE2 production. Together, these results support the model that PGE2 is required in the substrate and PGF2α required in the somatic cells to regulate mechanisms important for on-time border cell migration.
description: In summary, this thesis identifies two PGs required for border cell migration and cluster morphology, PGE2 and PGF2α. The thesis shows that PGs produced within the substrate contribute to collective cell migration, a source that is not well understood in the PG cell migration field. The thesis also identifies roles for PGF2α, an understudied PG in collective cell migration, in promoting on-time migration and controlling cluster morphology. These studies reveal border cell migration is an ideal system to identify and study the roles of PGs in the migratory cells versus their environment on cell migration. As these PGs and their mechanisms of action are widely conserved, these and future studies using border cell migration can increase the understanding of PGs during other migrations including those during development, wound healing and cancer metastasis.