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UBC Theses and Dissertations

Cellular and molecular mechanisms of action of NR2E1 in eye development Corso-Díaz, Ximena


NR2E1 is a highly conserved orphan nuclear receptor crucial for neural stem cell proliferation and maintenance during development and adulthood. Nr2e1-null mice have brain and eye malformations, display cognitive deficits, are aggressive, and blind. NR2E1 regulatory variants have been found in bipolar disorder and cortical malformations in humans. Complete understanding of NR2E1 action requires identification of genes regulated by NR2E1, protein partners including co-regulators that interact with NR2E1, and characterization of the loci where these interactions take place. Importantly, the mechanisms of action and regulation of NR2E1, and its role in human pathology remain poorly understood. In this thesis, I studied the role of NR2E1 in three different systems. First, I explored the potential role of NR2E1 mutations in patients with aniridia and other congenital ocular disorders. I found that mutations in NR2E1 do not play a role in aniridia and provided further evidence on the high genetic conservation of NR2E1 in the human population. Second, I studied the cell-autonomous and non-cellautonomous roles of Nr2e1 in retinal development using Nr2e1-null mice, and chimeric mice comprised of both wild-type and Nr2e1-null cells. I found that Nr2e1 regulates the development of specific retinal cell types and the organization of the neurites of inner nuclear neurons. Third, I studied NR2E1 at the protein level by screening for NR2E1 co-regulators using a peptide array and affinity purification tools. I found that the ligand binding domain of NR2E1 interacts with 19 putative novel co-regulators in vitro, and that most of these interactions are lost with the NR2E1 variant R274G, which I showed, does not affect gross retinal development in vivo. Overall, this study furthers our knowledge on the roles and mechanisms of action of NR2E1 during eye development by ruling out its role in a human eye disorder, demonstrating its role in mouse retinal cell development and lamination, and unraveling some of its potential co-regulatory partners. Future studies are necessary to better characterize the role of NR2E1 in cell development and neurite organization as well as its interaction with the co-regulators herein discovered during retinal and brain development.

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