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Title: Analyses of gene expression in Prn-p+/+ and Prn-p-/- mice
Author: Miele, Gino
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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The Transmissible Spongiform Encephalopathies (TSEs) are a group of invariably fatal neurodegenerative diseases which manifest in a broad range of species. At present, the causative agent of the TSEs remains unknown. The only disease-specific macromolecule identified to date is a protease-resistant abnormal isoform (PrPSc) of a protease sensitive normal host-encoded glycoprotein (PrPC). Despite the discovery of PrPC more than a decade ago, the precise normal physiological function of this protein remains unknown. PrPC is highly conserved across all species studied to date, and is expressed predominantly in neural tissues, but is also detected in non-neuronal tissues. PrP mRNA is developmentally regulated during embryogenesis, and has been shown to be widespread at E13.5. However, the precise timing of PrP mRNA transcriptional activation during murine embryogenesis has not been examined. Surprisingly, two lines of mice harbouring a null mutation in Prn-p, and which do not express detectable levels of PrPC, are viable and develop and reproduce apparently normally. This thesis describes attempts to obtain clues to the normal physiological function of PrPC by assessing the effect on gene expression of the ablation of PrPC. To identify genes with altered expression profiles as a result of the ablation of PrPC, the technique of Differential Display RT-PCR (DDRT-PCR) was optimised and utilised to undertake a comprehensive analysis of gene expression between Prn-p+/+ and Prn-p-/- postnatal developing brain. Five candidate genes were identified as being differentially expressed between Prn-p+/+ and Prn-p-/- brain. One of these genes was PrP, demonstrating the validity of the approach. The isolation, identification and expression of the remaining candidate transcripts is described. A detailed expression analysis of PrP mRNA expression was also performed and indicated that PrP is transcriptionally activated between E8.5 and E9 in the murine embryo, during neurulation. It was also demonstrated that PrP mRNA is developmentally regulated in the murine postnatal (P) developing brain, increasing in expression level approximately 8-fold from P0 to P42.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available