Date of Award

5-2024

Document Type

Campus Access Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Alexey Veraksa

Second Advisor

Kellee Siegfried-Harris

Third Advisor

Jens Rister

Abstract

The transcriptional repressor Capicua (Cic) regulates the development of the mammalian brain, lungs, and immune system and its dysfunction and dysregulation are causative in a panoply of human diseases including neurodegeneration and cancer. Few interactors have been identified that contribute to Cic’s function and regulation, and the mechanisms behind these processes remain unclear. Further identification and characterization of key Cic interactions is therefore necessary to elucidate these mechanisms and pinpoint targets for therapeutic development in associated diseases. I first aimed to further characterize the interaction between Cic and the ERK kinase, a known inhibitor of Cic function. Previous work in our lab identified several ERK-specific Cic phosphorylation sites, and I demonstrated that these sites are required for proper downregulation of Cic downstream of Torso receptor tyrosine kinase signaling during embryogenesis. Furthermore, I showed that these sites are also required for downregulation of Cic during neurodevelopment, leading to changes in neurobehavioral outcomes. I then performed a series of biochemical and genetic assays to elucidate and characterize the Cic interactome in mammalian cells and in vivo in Drosophila melanogaster. In mammalian cells, I conducted affinity purification mass spectrometry to identify proteins that interact with both human and Drosophila Cic. I posit that the conservation of these interactions suggests functional relevance. I then conducted a genetic screen to identify functional interactions that influence Cic-mediated wing development in Drosophila. I identified several interacting genes, including corepressors and components of complexes that remodel DNA accessibility. These findings contribute to the understanding of how Cic mediates repression and gains access to target DNA sites to repress transcription.

Comments

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