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Title: Elucidating transcription factor driven molecular cascades involved in embryonic neurodevelopment
Author: DeProto, Jamin
ISNI:       0000 0004 2728 7929
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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The brain is an incredibly complex organ composed of many cell types with intricate morphology, connectivity, and electrophysiological properties. Transcription factors orchestrate this elaboration by regulating numerous sets of genes and, in effect, the initial partitioning of gross functional areas of the brain and the eventual terminal differentiation of individual cells. Much is known about the expression patterns of individual transcription , factors, however, elucidating the exact mechanisms of transcription factor function has been , difficult because of their indirect regulatory relationship with genetic targets. '. I There are a few established methods for detecting direct transcription factor genetic targets. Chromatin immunoprecipitation and conditional knock-out mouse models are the most commonly utilized methods. Although there are advantages to such methods, they are challenging to implement, expensive, and prone to artifact. Over-expression of an electroporated transcription factor in cultured brain is shown to be an effective alternative. Tbr2 and Er81 were studied using over-expression in embryonic mouse. Subsequent expression changes were detected using gene micro array. Tbr2 appears to primarily target genes involved with cell cycle and metabolism (i.e. AgI, Uspll, Cdk-l, and Hes) while Er81 notably regulated genes associated with terminal differentiation (i.e. SIc18a3, Layn, and K v3.1). These findings fit with suspected functional significance of these transcription factors. However, some surprising results suggested other, unexpected roles. Tbr2 appears to interact with a few prominent angiogenic genes (Fgfr1, Sema6D, Mapk6, Epha3, and Ctnnb1). It was found that Tbr2 expressing neuroprogenitors tend to associate with blood vessels and is suggestive of a novel relationship establishing a neurovascular-neuroprogenitor niche at least partly regulated by Tbr2 regulated genes. Additionally, Er81 appears to down- regulate Ctip2 and up-regulate Tshz2. Taken together, a mechanism begins to take shape where axonal projections within the cerebral hemispheres are increased by way of Er81 regulation of Ctip2 and Tshz2. Overall, these results show that the method can identify genetic targets of transcription factors and a useful tool for understanding mechanisms of development, including novel relationships between seemingly disparate cell types.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available