UBC Theses and Dissertations
Evaluating the effects of variable NR2E1 levels on gene expression, behaviour, and neural and ocular development Wong, Bibiana (Ka Yan)
Nuclear receptor 2E1 (Nr2e1) is expressed in the developing and adult brain and eye, and controls proliferation and differentiation of neural and retinal stem/progenitor cells by regulating genes important in these cellular processes. The Simpson laboratory discovered and characterized a spontaneous deletion of mouse Nr2e1 (the fierce allele, frc) and demonstrated the functional equivalence of human and mouse NR2E1 when the behavioural and neuroanatomical phenotypes of Nr2e1frc/frc mutants were rescued by introducing human NR2E1. NR2E1 has recently been implicated in human psychiatric disorders and variants in NR2E1 were identified in patients with brain and behavioural abnormalities, including bipolar I disorder (BPI). Although NR2E1 had been implicated in BPI, the validity of Nr2e1frc/frc mice to model BPI has not yet been tested. In anticipation of subtle behavioural phenotypes, the hypothesis that dark-phase testing affects the outcome of high-throughput behavioural tests was tested. We demonstrated that dark-phase testing improved discrimination between genetically distinct inbred mouse strains. This result was integrated into the experimental design for evaluating Nr2e1frc/frc mice as a model for BPI by behavioural measures and lithium treatment. Nr2e1frc/frc mice exhibited behavioural traits used to model BPI in rodents, including hyperactivity and learning deficits; however, adult Nr2e1frc/frc mice were resistant to the effects of lithium treatment, and therefore our results did not provide support for Nr2e1frc/frc mice as an appropriate pharmacological model for BPI. Since the nature of patient variants in NR2E1 is likely regulatory, resulting in transcriptional alterations, and the effects of variable levels of Nr2e1 are currently unknown, I tested the hypothesis that variable Nr2e1 levels will affect gene expression and neurological and ocular development. Mice overexpressing Nr2e1 showed alterations in transcription levels of key target genes in both the brain and the eye, significant increase in neural stem/progenitor cell proliferation in the subventricular zone of the adult brain, and severe eye abnormalities. Gene expression changes in Gfap, Gsk3β, Pax6, and Nr2e3 suggest a role for Nr2e1 in genetic pathways important in psychiatric and eye disorders, including BP, Alzheimer Disease, cancer, Aniridia, and enhanced S-cone syndrome. Collectively, these results justify the further investigation of NR2E1 in these human disorders.
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