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Title: Development of a chick embryo model to study important regulatory domains of human genes implicated in Motor Neurone Disease
Author: Khursheed, K. N.
ISNI:       0000 0004 6495 5252
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Motor neurone disease refers to a group of neurological disorders that result from progressive degeneration of the motor neurones leading to death from respiratory failure within 3-5 years from the onset of symptoms. Amyotrophic lateral sclerosis (ALS) is one of the most common forms of motor neurone disease, and can be described as entailing the involvement of both upper and lower motor neurones. Usually, the disease is obvious and presents as asymmetrical weakness in the limbs and progressive muscular atrophy. Over the last two decades more than 30 genes have been identified as involved in ALS pathology. These include PARK7 and FUS (Fused in sarcoma) which are the subject of this thesis. FUS is a multifunctional protein that has ubiquitous expression and is involved in different steps of RNA processing such as mRNA and miRNA. 10% of ALS cases are heritable and mutation of the FUS gene is found in 3-5% of familial forms of ALS. Therefore the FUS gene is important for it association as a candidate gene that is postulated to be important for ALS, in addition to various types of cancer. Mutations with FUS gene have been found in autopsy samples from the brain and spinal cord of patients with ALS. Understanding the regulation of FUS gene expression may, therefore, give insights into how its stimulus inducible expression may be associated with neurological disorders. My hypothesis is that the evolutionary conserved regions (ECRs) and primate specific retrotransposons of the SINE-VNTR Alu (SVA) are regulatory domains from the human FUS gene and PARK7 genes. Consequently, the aim of this thesis was to develop an in vivo model to validate their regulation. Comparative genomic analysis was used between distant species, utilizing the ECR browser and UCSC browser to identify conserved regions from the FUS gene. It is demonstrated that ECR and SVA, xviii which can drive reporter gene activity in vitro (in the neuroblastoma cell line), are also capable of driving reporter gene expression in the chick embryo neural tube and brain at embryonic day 5. In conclusion, these identified important ECRs from human FUS gene act as regulatory domains. In addition, the SVAs, representing the most recent retrotransposon to enter the human genome also was showed to have regulatory properties in FUS and PARK7 genes. Furthermore, the thesis demonstrates that these elements regulate gene expression in vitro and in vivo. This supports the idea that employment of the chick embryo as a useful and informative model system to analyse mammalian gene regulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral