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An Investigation on the Modulation of Signalling Transduction Pathways during Early Xenopus Development
[Thesis]. Manchester, UK: The University of Manchester; 2013.
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Abstract
The thesis titled Investigation of signalling transduction during early Xenopus embryogenesis (thesis) has been composed and redacted by Siwei Zhang. The final version was submitted to the University of Manchester for the degree of Doctor of Philosophy (PhD) in the Faculty of Life Sciences on January 2013.The primary aim of my PhD thesis was to identify and characterise novel modulators of intracellular signalling during early vertebrate development. The first phase of my thesis was to design and execute a large-scale gain of function screen in order to identify novel modulators of various important signal transduction pathways during early Xenopus development. From this screen I identified twenty novel of growth factor signalling. In the second phase of my PhD study, I concentrated on the characterization and mode of action of one of the genes I identified in the screen; namely fezf2. I showed that Fezf2 regulates neurogenesis in the diencephalon by locally promoting Wnt signalling through repression of lhx2 and lhx9. Notably, this investigation on the function of fezf2 not only revealed the previously undiscovered role of fezf2-mediated Wnt regulatory mechanism during diencephalon development, but also confirmed our in vivo screening approach in identifying potential regulators of signalling pathways. To the end, my PhD project has provided me with a fruitful journey of discovery, which started with the design and execution of a large-scale screen, ending with the detailed characterization of a factor involved in the modulation of signalling and forebrain development. This study is has broadened our understanding of how intracellular and extracellular signals are integrated during embryonic development process, which forms an interactive network ultimately resulting in appropriate cell differentiation, organ formation, and regional patterning.
Layman's Abstract
Head development, including craniofacial and brain development, is crucial for proper brain function upon growth. Any mis-regulation during head development usually resulted in severe head defects in the head and associated structure, such as cleft-lip/palate, microcephaly, septo-potic dysplasia, which all are very difficult for treatment with current medical knowledge and technique. Considering the vital role of head for proper body functioning, multiple regulatory machineries have been imposed to ensure the face and brain will grow in a properly controlled manner. In this proposal, we will investigate the molecular mechanisms that determine brain development during early embryo development. Frog embryos are large, easily manipulated, and develop in an aquatic environment that allows easy observance. More importantly, the brain structure of Xenopus is highly comparable to that of humans. In addition, key genetic machineries that determine forebrain development are highly conserved between Xenopus and human. Thus, we consider our investigation results would provide invaluable knowledge in treatment of early brain defects in human.