Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Lajoie, Patrick

2nd Supervisor

Renaud, Stephen J.

Co-Supervisor

Abstract

The placenta supports the exchange of nutrients and gases between mother and fetus. Trophoblasts are the parenchymal cells of the placenta and perform the vast majority of its functions. There are different types of trophoblasts derived from stem cells called cytotrophoblasts (CTs). The balance between CT proliferation and differentiation is important for placental development. OVO-like 1 (OVOL1) is a transcription factor expressed in many epithelial lineages undergoing differentiation, including human differentiating CTs. The molecular mechanisms through which OVOL1 represses proliferation and/or promotes differentiation are unknown. We hypothesize that OVOL1 interacts with specific HDACs to repress CT proliferation. Ectopically expressing OVOL1 in wild-type yeast caused a significant growth defect, this defect was rescued by deleting class II HDACs. Ectopically expressing OVOL1 in human CT cell-line (BeWo) caused a significant increase in expression of ERVFRD1, a gene associated with cytotrophoblast differentiation, indicating that expression of OVOL1 is sufficient to trigger upregulation of at least a subset of genes that regulate CT proliferation and differentiation. Together, our findings demonstrate that OVOL1 can repress cell proliferation in yeast, a feature requiring specific HDACs, and is sufficient to at least prime CT differentiation. The combination of yeast and mammalian models provides a new experimental platform to better characterize OVOL1 function in repressing CT differentiation, providing new insights into placental development and potential therapeutics for placenta-associated diseases.

Summary for Lay Audience

During pregnancy, the placenta forms to facilitate the exchange of gases and nutrients between the mother and baby. When abnormal placental development occurs, complications can arise leading to serious harm to both the mother and baby. During the initial stages of pregnancy, important steps have to take place to ensure proper placental development. Formation of a specific placental cell-type that controls nutrient and gas exchange is regulated by a protein known as OVO-like 1 (OVOL1). However, there is very little known about how OVOL1 functions to form this important cell-type. Therefore, my goal is to explore the underlying mechanisms by which OVOL1 acts and how it works to trigger placental cells to undergo specialization and form different cell types. Therefore, my main aim is to explore the underlying mechanisms by which OVOL1 acts. I will be using yeast as a model organism to understand how OVOL1 affects gene expression. Yeast are single-celled eukaryotic organisms that share many homologous genes with humans, and allow us to conduct rapid, controlled experiments to identify how OVOL1 affects gene regulation. I hope to identify gene and protein targets that can act as future therapeutic targets to address placental maldevelopment. Future work will identify factors that affect OVOL1 function in yeast and translate our findings into mammalian models. My findings will provide insight into how the placental forms, which will help us better understand the causes of various pregnancy complications.

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