Uncovering a Fundamental Mechanism Underlying Female Oocyte Quality and RASopathies Using C. elegans as a Model System

Han Bit Baek, BS (Advisor: Swathi Arur, PhD)

Signaling pathways are molecular networks that allow cells to communicate between and within themselves. They are crucial for the coordination of diverse cellular processes and are the molecular mechanism in which cells sense and respond to their environment. RAS (Rat Sarcoma) is a small GTPase that transmits extracellular growth factor signals through a downstream kinase cascade and ERK (Extracellular-signal regulated kinase) is the terminal kinase, and it controls cellular processes such as proliferation, differentiation, and survival by phosphorylating its downstream effectors. This post translational modification regulates the effector by modulating its activity, levels, and/or interaction with other molecules. Given the dynamic nature of cells, such modifications must be reversible to allow cells to build and to breakdown cellular components such as the nucleus during cell division. Therefore, constitutive activation of the RAS/ERK signaling pathway can lead to adverse outcomes such as cancers and birth defects that are known as RASopathies.

The RAS/ERK signaling pathway regulates oocyte development and maturation across species. In Caenorhabditis elegans (C. elegans), ERK activity switches between sustained activation during oocyte formation and inactivation during oocyte maturation, fertilization, and early embryogenesis. Consequences of ectopic ERK activity upon oocyte maturation and in early embryogenesis are unknown. Using C. elegans, I show that ectopic ERK activity upon oocyte maturation results in embryos with abnormalities in nuclear divisions leading to embryonic death. I uncover that ERK directly phosphorylates Polo-like kinase 1 (PLK-1), a master regulator of cell division, on Serine 404 to inhibit nuclear envelope breakdown (NEBD) in early embryogenesis. The RAS/ERK/PLK-1 pathway poisons zygotic NEBD and inhibits the merging of parental genomes, underlining the importance of turning off ERK prior to embryogenesis. Given the conserved nature of both ERK signaling to oocyte development and PLK1 to embryonic divisions, this work has implications for women undergoing in vitro fertilization (IVF) where ectopic ERK activation during superovulation through hormonal stimulation may diminish oocyte quality and influence zygotic development.

Advisory Committee:

• Swathi Arur, PhD, Chair
• Francesca Cole, PhD
• George Eisenhoffer, PhD
• Michael Galko, PhD
• Yejing Ge, PhD
• Zheng Zhou, PhD

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