Kimberley Gauthier, Molecular Genetics

Supervisor:
Dr. Julie Brill, Senior Scientist, Cell Biology Program, The Hospital for Sick Children, and Professor, Department of Molecular Genetics, University of Toronto

PhD Thesis Title:
In vivo analysis of the LIN-2/7/10 complex in spatial regulation of LET-23 EGFR signalling C. elegans

PhD Thesis:
Scaffolding proteins play a central role in spatial regulation of signaling cascades, which ensures proper timing, localization, and activation of signaling during development. The nematode Caenorhabditis elegans relies on polarized localization of the Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase that is frequently overactivated in human cancers, for normal signaling activation and cell fate specification during vulva development. During my PhD, I studied the mechanism through which an evolutionarily conserved complex consisting of LIN-2 (CASK), LIN-7 (Lin7a), and LIN-10 (APBA1) (the LIN-2/7/10 complex) maintains EGFR localization to ensure normal vulva development. My research revealed novel Golgi-associated pathways through which these proteins work both as a complex, and also independently of each other, to coordinate polarized trafficking, cell signaling, and development.

Current Research:
During the development of a multicellular organism, epidermal tissue wraps around the embryo and forms a seamless seal, resulting in a continuous epithelial sheet. A prime example is dorsal closure in Drosophila, a fruit fly model organism, in which lateral epidermal cells wrap around the developing embryo and join together along its back. Dorsal closure is driven by similar cellular mechanisms as wound healing: activation of the Jun Kinase (JNK) signaling pathway, and contractions of the actin cytoskeleton (structural filaments that control cell shape and movement of structures and proteins within a cell). Still, our understanding of how cells synchronize their movements and coordinate cellular processes to seal up a hole in an epithelial sheet is incomplete. Work from the Brill and Harden labs found that lipid phosphatase Sac1 is necessary for dorsal closure, possibly due to its requirement for restricted JNK signaling, myosin expression, and cytoskeleton contractility. Throughout my postdoctoral work, I will study the role of Sac1 and of phospholipids during dorsal closure in Drosophila by testing how Sac1 activity is regulated, the mechanism through which Sac1 inhibits JNK signaling, and how Sac1 coordinates cytoskeletal function. These studies will uncover key requirements for phospholipid regulation in mediating cellular and tissue dynamics during development.

Scholarships/Awards:
My graduate research was supported by Master’s and Doctoral scholarships from the Fonds de Recherche du Québec – Santé (FRQS), by a Master’s Canada Graduate Scholarship from the National Science and Engineering Research Council (NSERC), and a Doctoral Post-Graduate Scholarship from NSERC.

Publications:

1. Gauthier KD, Rocheleau CE (2021). Dynamic expression and localization of the LIN-2/7/10 protein scaffolding complex during C. elegans vulval development. Development, 148: dev194167 doi: 10.1242/dev.194167
2. Gauthier KD, Rocheleau CE (2021). LIN-10 can promote LET-23 EGFR signaling and trafficking independently of LIN-2 and LIN-7. Mol Biol Cell, doi:1-.1091/mbc.E20-07-0490.
3. Gauthier K, Rocheleau CE (2017). C. elegans Vulva Induction: An In Vivo Model to Study Epidermal Growth Factor Receptor Signaling and Trafficking. In: Wang Z. (eds) ErbB Receptor Signaling. Methods in Molecular Biology, vol 1652. Humana Press, New York, NY.
4. Skorobogata O*, Meng J*, Gauthier K, Rocheleau CE (2016). Dynein-mediated trafficking negatively regulates LET-23 EGFR signaling. Mol Biol Cell, doi:10.1091/mbc.E15-11-0757.
5. Hoang C, Ferraro-Gideon J, Gauthier K, Forer A (2013). Methods for rearing Mesostoma ehrenbergii in the laboratory for cell biology experiments, including identification of factors that influence production of different egg types. Cell Biol Int, 37(10): 1089-1105.