Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biology

Supervisor

Dr. Thomas Drysdale

Abstract

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Successful patterning of the embryo, from establishing the three primary axes to the regional specification of tissue progenitors is essential to generating a viable embryo. The three germ layers in the early embryo undergo patterning through slightly different mechanisms. The tissue of interest to this study is the lateral plate mesoderm (LPM), which will give rise to the lineages of the cardiovascular system and is essential for regional specification of adjacent germ layers. However, little is known about how the LPM itself undergoes regional specification and attains its intitial patterning after gastrulation. Here, I will demonstrate that a complex pattern of gene expression exists across the entire LPM shortly after gastrulation, much earlier than previously recognized. Furthermore, I will use molecular techniques to elucidate the signalling factors involved in the early patterning and regional specification the LPM. I hypothesize that both the retinoic acid (RA) and Fibroblast Growth Factor (FGF) signalling pathways are involved in the LPM regional specification in the neurula stage embryo. Through the use of exogenous modulators of the RA pathway, I will show that RA signalling is essential for patterning the anterior-dorsal and middle LPM domains. Secondly, by addition of a synthetic FGF receptor inhibitor I will demonstrate that FGF signalling is essential for establishing the anterior-ventral and posterior domains of the LPM and functions antagonistically to the RA pathway. I will also show that altering the activity of either of these two signalling pathways affects the specification of the early cardiovascular progenitors, particularly the cardiac and endothelial lineages. Finally I will provide preliminary evidence that one of the early LPM marker genes, Hand1, is necessary for normal cardiovascular development and thus provide a link between the early LPM pattern and later organogenesis. A thorough understanding of the mechanisms behind specifying embryonic lineages is of vital importance for basic biological knowledge, as well as for providing a basis for the emerging field of regenerative medicine, whereby researchers are attempting to generate organ progenitors in vivo to be used for cell therapies.

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