Dissertation
The role of ATGL-mediated lipolysis during collective cell migration in Drosophila
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008461
Abstract
Collective cell migration is the orchestrated movement of groups of cells to specific locations. Collective cell migration is essential for the development and maintenance of multicellular organisms. Cells must migrate collectively to precise locations to form tissues and organs during embryogenesis. Following injury, cell migration is a vital part of the wound healing process. Collective cell migration is also a complex and carefully regulated process. When dysregulated, improper cell migration contributes to a variety of diseases ranging from congenital birth defects to cancer metastasis. Understanding the mechanisms that regulate collective cell migration is therefore essential for developing new therapies for a range of diseases. My thesis project focuses on understanding the role of lipid droplets (LDs) during in vivo collective cell migration.
LDs are critical organelles for lipid and energy homeostasis across organisms. LDs have emerged as an important factor during cancer cell migration. In several types of cancer, LDs serve as a reservoir of fatty acids that can be metabolized to power the energy-intensive processes of invasion and migration. However, it is not known whether LDs have a general role in promoting collective cell migration, or whether their role is unique to metastatic cancer cells. Further, the studies that defined the role for LDs during cancer cell migration primarily used in vitro migration assays. As such, our understanding of LDs during in vivo migration is very limited. To uncover the role of LDs during in vivo collective cell migration, we use as our model the migration of the border cells during Drosophila oogenesis.
Border cell migration is a powerful in vivo model of invasive, collective cell migration which has been used to uncover many conserved mechanisms of migration. This developmental migration occurs during Stage 9 of Drosophila oogenesis. At the beginning of Stage 9, two polar cells at the anterior of the follicle recruit 6-8 nearby follicle cells to become the border cells. Once specified, the border cells round up to form a cluster and delaminate from the anterior epithelium. Driven by multiple chemotactic signals, the border cell cluster invades the adjacent germline-derived nurse cells and migrates collectively toward the oocyte at the posterior end of the follicle. This migration is essential for Drosophila fertility, as the border cell cluster ultimately contributes to the formation of the micropyle.
In Chapter 2, I present data revealing that the border cells store fatty acids in LDs, and that the release of fatty acids from LDs via lipolysis must be carefully controlled for normal delamination and on-time migration. Specifically, the morphology of border cell LDs changes throughout the migratory process, with LDs becoming smaller and more numerous by the end of migration. These findings suggest that LD biogenesis and LD lipolysis are both active processes in the border cells. Next, I identify adipose triglyceride lipase (ATGL) as a critical regulator of LD volume in the border cell cluster. ATGL mediates the first step of lipolysis, the hydrolysis of triglyceride into glycerol and free fatty acids. Importantly, loss or border cell-specific reduction of ATGL results in failure to detach (i.e., delaminate) from the anterior epithelium and delayed migration. These findings reveal that ATGL and LD lipolysis are essential for the initial invasion and the collective migration of the border cell cluster.
Next, I present data revealing that the border cells are sensitive to the amount of ATGL present. Border cell-specific overexpression of ATGL dramatically depletes LDs in the border cells, presumably due to excess lipolysis. Importantly, ATGL overexpression leads to migratory defects similar to those upon loss or reduction of ATGL, including failed detachment and delayed migration. Together, these findings demonstrate that successful border cell delamination and migration depend on proper storage and utilization of LD-stored fatty acids.
Lastly, I provide evidence that mitochondrial fatty acid oxidation is important for border cell migration. Fatty acids released from LDs can fulfill many purposes during cell migration, including serving as metabolic substrates in the mitochondria for energy production. Supporting that LD lipolysis provides fatty acids to the mitochondria, loss of ATGL disrupts mitochondria morphology and function. Specifically, loss of ATGL results in excessive mitochondrial clustering in the border cells. Additionally, loss of ATGL decreases relative mitochondrial membrane potential and increases the production of reactive oxygen species. Together, these findings support that ATGL-mediated lipolysis is essential for supporting mitochondrial function and health in the border cells. Finally, I find that carnitine palmitoyltransferase 1 (CPT1) is essential for border cell delamination. CPT1 is a long-chain fatty acid importer and a rate-limiting enzyme for mitochondrial fatty acid oxidation. Loss of CPT1 severely blocks border cell detachment from the epithelium. This finding supports that fatty acid import into the mitochondria is essential for border cell delamination and subsequent migration.
In summation, this thesis establishes border cell migration as a powerful in vivo model for the study of LDs and fatty acid oxidation during invasive, collective cell migration, including during the initial process of delamination. This thesis demonstrates that ATGL-mediated lipolysis promotes a normal, developmental migration, strongly supporting that LD storage and utilization has an evolutionarily conserved role during collective cell migration—a role that has likely been co-opted by metastatic cancer cells to promote their own migration. Thus, LDs have critical roles in promoting collective cell migration across diverse contexts and could represent a novel target for the development of new therapies for a range of diseases.
Details
- Title: Subtitle
- The role of ATGL-mediated lipolysis during collective cell migration in Drosophila
- Creators
- Israel Jacob Wipf
- Contributors
- Tina L. Tootle (Advisor)Martine Dunnwald (Committee Member)Yumi Imai (Committee Member)Ling Yang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cell and Developmental Biology)
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008461
- Publisher
- University of Iowa
- Number of pages
- xx, 176 pages
- Copyright
- Copyright 2026 Israel Jacob Wipf
- Language
- English
- Date submitted
- 04/14/2026
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 148-176).
- Public Abstract (ETD)
Cell migration, defined as the directed movement of cells to specific locations, is a fundamental process for the development and maintenance of multicellular organisms. The migration of skin cells, for instance, is vital for the wound healing process after injury. Cell migration must also be carefully controlled, as improper migration contributes to many diseases. Congenital birth defects can arise as the result of improper cell migration during embryonic development. Further, cell migration is a crucial step in the process of metastasis, the spreading of cancer cells from the primary tumor to distant organs, which is the primary cause of death for cancer patients. An emerging factor in cell migration are lipid droplets, specialized organelles for storing lipids including fatty acids. Lipid droplets have been shown to promote the migration of cultured cancer cells. My thesis project is focused on understanding whether lipid droplets have a conserved role in cell migration, including during normal, developmental migrations inside living organisms. To address these questions, I use a developmental model of collective cell migration called border cell migration. During Drosophila oogenesis, the border cells undergo a temporally defined migration in between an adjacent tissue to reach the oocyte. I find that the border cells store fat in lipid droplets, and that the careful release of fatty acids from lipid droplets is essential for border cell delamination—the initial process of detachment from the epithelium—and for the completion of their migration on time. Further, I identify the protein adipose triglyceride lipase (ATGL) as an important regulator of fatty acid release from lipid droplets during border cell migration. Finally, I propose that fatty acids are trafficked from lipid droplets to mitochondria to provide energy for border cell delamination and migration. Together, these findings support that lipid droplets have an evolutionarily conserved role in collective cell migration and may be specifically required to provide energy for the process of delamination.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9985176872602771
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