Date of Award

12-31-2016

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Alexey Veraksa

Second Advisor

Richard Kesseli

Third Advisor

Linda Huang

Abstract

The regulation of organ growth is a fundamental aspect of developmental biology. My work uses Drosophila as a model system to understand how the various growth regulators are coordinated. The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers and neurodegenerative diseases. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. In order to identify Cic regulators, I have used affinity purification/mass spectrometry (AP-MS) to study the Cic protein interactome in Drosophila S2 cells and embryos. I have found that the kinase Minibrain (Mnb, Drosophila ortholog of Down syndrome kinase DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Downregulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. This work has uncovered a previously unknown mechanism of downregulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, since DYRK1A and CIC exhibit, respectively, pro-oncogenic versus tumor suppressor activities in human oligodendroglioma, my results raise the possibility that DYRK1A may also downregulate CIC in human cells.

Available for download on Sunday, December 31, 2017

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