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Title: The role of lin28, an FGF signalling target, in development and miRNA regulation
Author: Warrander, Fiona
ISNI:       0000 0004 2732 9332
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2012
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The related genes lin28a and lin28b code for conserved RNA-binding proteins, which contain two key RNA-binding motifs that determine their functions. Previously, our laboratory identified lin28a as a putative downstream target of FGF signalling in the early Xenopus embryo. This was found to occur at gastrulation stage, during which key signalling pathways such as the FGF pathway are active in specifying germ layer development. lin28 is a heterochronic gene in C. elegans and controls the timing of developmental events. In vertebrates, the lin28a gene shows pluripotent-specific expression, and has come to particular interest as one of four factors used to successfully re-program differentiated somatic cells into induced pluripotent stem cells. Both lin28a and lin28b have a high prevalence of ectopic expression in cancer. A well characterised target of both lin28a and lin28b is the microRNA let-7, inhibiting biogenesis to the mature microRNA form. The lin28 proteins have also been shown to potentiate translation of numerous mRNA targets. The aim of this project was to identify if lin28 has an important developmental role in vertebrates. Work in the Xenopus tropicalis embryo found that both lin28a and lin28b were targets of FGF signalling at gastrulation, and were required for correct germ layer patterning at this stage. In order to explore conservation in humans, mesenchymal stem cells were used to model the effects of FGF signalling upon the mesodermal germ layer, and whether lin28 played a role in this. Additional pluripotent cell models were investigated for their suitability in which to study lin28 function. Analysis of lin28 targets in Xenopus revealed that the miR-17-92 cluster family of miRNA may be positively regulated by the lin28 proteins, with a direct interaction possible with a member of these: pre-mir-363. These miRNAs may have further important developmental roles in response to this regulation by the lin28 proteins.
Supervisor: Isaacs, H. V. ; Genever, P. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available