Elizabeth Simpson


Research Classification

Congenital Anomalies
Eye and Visual System Diseases

Research Interests

Gene therapy for brain and eye diseases
In vivo gene augmentation and genome editing (CRISPR/CAS9)
Rare diseases
Congenital blindness
MiniPromoters for restricted expression

Relevant Degree Programs


Research Methodology

Humanized mouse models of disease
Recombinant adeno-associated virus (rAAV)


Postdoctoral Fellows
Any time / year round

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2019)
rAAV9 mediated PAX6 gene transfer temporarily reverses corneal epithelial thinning in a mouse model of aniridia (2018)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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Cellular and Molecular Mechanisms of Action of NR2E1 in Eye Development (2014)

No abstract available.

Development of tools in mouse for future gene therapy: Promoters for the CNS, and novel expression models of neural stem cell regulator, NR2E1 (2013)

Three challenges exist for human neurobiology, specifically in the areas of genomics and geneticmedicine: understanding of genome regulation, understanding of central nervous system (CNS) development,and the lack of promoters for human gene therapy. To address these issues, we used computational biologystrategies, primarily involving phylogenetic footprinting, to identify putative regulatory elements in genes with aregionalized or cell-type specific expression pattern. We generated human MiniPromoter constructs, less than 4kilobases in size, and made genetically engineered mice by single-copy knock-in at the mouse Hprt locus.Neuroanatomical analyses were performed on brain and eye, primarily. Using this strategy, we generated 50novel MiniPromoters for use in driving gene therapy constructs. Lastly, we demonstrated retained specificity ofthree retinal ganglion cell layer MiniPromoters when these were moved from knock-ins to an adeno-associatedviral vector, exemplifying the utility of these constructs in other systems. In order to study CNS development, wechose to functionally analyze non-endogenous expression of the neural stem cell regulator NR2E1 in mice. Weemployed a DCX-based MiniPromoter from the Pleiades Promoter Project, in addition to the ubiquitous CAGpromoter, to drive ectopic and ubiquitous expression of human NR2E1. DCX-based expression of human NR2E1did not result in any overt phenotypes and was unable to rescue the brain and eye defects observed in Nr2e1frc/frcmice. In contrast, the CAG promoter resulted in embryonic death at ~E8, with failure of neural tube closure. Weshowed that expression of NR2E1 has negative effects on embryonic stem cell growth. Furthermore, weobserved altered Pax6 expression in NSCs and embryos. Future work on promoter design and NR2E1 biology willadvance our knowledge of genome regulation and CNS development.

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The use of novel humanized mouse models and transcriptome characterization to study the neurogenesis factor, NR2E1, in brain and eye development (2013)

No abstract available.

Evaluating the Effects of Variable NR2E1 Levels on Gene Expression, Behaviour, and Neural and Ocular Development (2010)

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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Master's Student Supervision (2010 - 2018)
A Mutation Screen of NR2E1 in Patients with Anirida, Peters' Anomaly, and Related Eye Disorders (2010)

Aniridia is a rare genetic panocular (whole eye) disorder which, for the majority of cases, is caused by mutations or chromosomal rearrangements involving paired box gene 6 (PAX6). Peters’ anomaly (PA), also a genetic eye disorder, has also been found to be associated with mutations in PAX6, and also in FOXC1, PITX2, and CYP1B1. However, in approximately 20% of patients who have aniridia and 75% of patients with PA, no mutation has been found in PAX6, or other genes involved these eye disorders, and for these patients, their genetic mutation is unknown. This precludes these patients from genetic testing and thus, from gaining the benefits from genetic counseling and early medical interventions. My hypothesis was that patients who have aniridia, Peters’ anomaly or related eye disorders, for which genetic cause is unknown, have mutations in NR2E1. The purpose of this thesis was to study patients with aniridia, Peters’ anomaly, and related eye disorders in order to identify mutations in a novel candidate gene, NR2E1. Here, the first germline amino acid change was identified in the NR2E1 gene in a patient with Peters’ anomaly and his mother, and not found in 392 control subjects. The identification of an amino acid variant in NR2E1 is significant as it supports the hypothesis that NR2E1 is a regulator of eye development in humans and has implications for the gene in the development of eye disorders. If future analysis leads to the identification of NR2E1 mutations in additional patients, it will allow patients with eye disorders of otherwise unknown genetic etiology to receive the benefits of modern genetic medicine and genetic counseling. This future work endeavors to provide the scientific and medical community with a greater depth of knowledge of the role of NR2E1 in genetic eye disorders.

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