The Role of Sox18 in Blood Vessel Development

Meredith Downes (2008). The Role of Sox18 in Blood Vessel Development PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

       
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Author Meredith Downes
Thesis Title The Role of Sox18 in Blood Vessel Development
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
Publication date 2008-04
Thesis type PhD Thesis
Supervisor Prof. Peter Koopman
Prof. George Muscat
Total pages 263
Total colour pages 25
Total black and white pages 238
Subjects 270000 Biological Sciences
Formatted abstract SOX transcription factors display complex, overlapping expression patterns throughout
embryogenesis. These patterns reflect their diverse roles within the development of
many embryonic organ and tissue systems. The homologous Group F SOX factors,
SOX7, -17 and -18, are expressed in the endothelial components of the developing
cardiovascular system. Previous studies of Sox18 and -17 have provided some insight
into the role of Sox factors in vascular development. Yet, the molecular and cytological
events orchestrating Sox function in this context remain incompletely understood. This
thesis describes research intended to shed further light upon Sox function in vascular
development. It includes the study of two mutant mouse models of Sox18 and the
investigation of a new downstream target gene.
The Ragged Opossum (RaOp) mutant was originally hypothesised to be the most severe
Sox18 mouse mutant model. Researchers had described the RaOp to be homozygous
lethal prior to 11dpc, based upon Mendelian ratios of phenotype. However, through
genotyping, the homozygous RaOp mutant is shown to predominantly survive until
14.5dpc. The edema and enlarged vessels exhibited by the RaOp homozygotes from
12.5dpc suggest Sox18 is primarily required much later in cardiovascular development
than previously hypothesised. The vasculature of the RaOp homozygous embryo was
analysed using histology, electron microscopy, dye injection analysis and
immunofluorescence. These studies indicate that RaOp vessel enlargement is associated
with endothelial hyperplasia and rupture and decreased pericyte recruitment. Upon this
basis, it is hypothesised that Sox18 has a role in vessel maturation.
A comparison of the phenotype of the RaOp homozygote with known mutant models of
vascular factors led to the identification of Tie1 as a potential downstream regulatory
target of Sox18. This hypothesis was investigated through a comparison of expression
patterns using in situ hybridisation, the identification and testing of potential Sox18
binding sites within the sequence of the Tie1 promoter, and the assay of Sox18
regulation of the Tie1 promoter in cell culture and mutant animal models. In this
manner, it is shown that Sox18 is able to upregulate the Tie1 promoter and that the
RaOp mutant form of Sox18 inhibits this regulation.RaOp mutant Sox18 is hypothesised to act in a dominant negative manner and
potentially inhibit not only Sox18 function, but also that of the putative functionally
redundant factors, Sox7 and -17. This hypothesis and its ramifications for Sox
regulation of vascular development are explored through the creation of a compound
RaOp/ Sox18 null mutant, the inbreeding of the Sox18 null mutant on the C57BL/6J
background and the investigation of Sox7 and -17 regulation of Tie1. Both Sox7 and -17
are shown to upregulate the Tie1 promoter in cell culture assays, suggesting that these
factors could be involved in Tie1 regulation and the cause of some RaOp defects. Yet
preliminary investigation of both the compound Sox18 null/RaOp mouse mutant and the
F8 C57BL/6J Sox18 null heterozygous mutant demonstrated a comparable but less
severe phenotype to the RaOp homozygote. As these models are specifically Sox18-
deficient, it is probable that the RaOp mutant model is representative of Sox18
dysfunction in vascular development and, hence, that Sox18 has a role in vessel
maturation.
Keyword Sox, Ragged, blood vessel development, vessel maturation, mouse mutants.
Additional Notes Colour pages: 31, 37, 55, 81, 85, 89, 95, 99, 103, 109, 115, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 185, 189, 193, 197. Colour pages predominantly have a blank page following them, in order to keep the page numbers correct if they are being printed on a separate colour printer. (the only colour pages with no blank page following is on page 55). It is preferred to print the whole thesis on the one printer and not print colour pages separately. If it is necessary to print the colour pages on a separate printer, the blank pages immediately following the colour pages should not be printed in the black and white pages as they correspond to the back of the colour pages.

 
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Created: Thu, 06 Nov 2008, 13:24:46 EST by Ms Meredith Downes on behalf of Library - Information Access Service