published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

117 leaves : ill. ; 29 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1975

Thesis (Ph. D.)--University of Adelaide, Dept of Science, 1987. / Includes bibliographical references (leaves 154-185).

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available in print.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1975.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

The aim of this study was to investigate the role of signalling molecules during the development of the chick limb. First, it was demonstrated that a functional gradient of bioactive FGFs is present down the limb from distal to proximal. This functional FGF gradient decreased at stage 26, at the time of AER regression. Although morphogenetic gradients are of considerable theoretical importance in developmental biology, there are rather few practical demonstrations of their existence. The effects of prolonging the presence of active FGF on limb pattern formation were investigated. Application of ectopic FGF-4 to the distal tip of the limb at stage 26 had a number of effects on limb development. In particular, the cartilage structure conventionally labelled element "5" increased in size and in some instances acquired a digit-like morphology. The evolutionary considerations of this finding are briefly considered. Analysis, including 3D computer reconstruction, of the musculature and vasculature of limbs after FGF implants was carried out in the hope of establishing the identity of this digit like element. This proved not to be possible. However, both muscle mass and vascularisation had increased after the procedure. Known molecular pathways involving the proximo-distal patterning of the limb were then investigated. Whole mount in situ hybridisation studies were carried out with respect to FGF-4, sonic hedgehog, Hoxd-11 and FGF-8. These revealed that the shh/ FGF positive feedback loop was not involved in these changes. FGF-8 expression in late stage AERs was markedly increased. Hoxd-11 expression was not affected by ectopic FGF implants. Together, these findings suggest that the effect of FGF implants is mediated by a novel mechanism. The effect of FGF-4 implants on programmed cell death in the limb was examined. At stage 28 anterior necrotic zone was larger, and had shifted distally. However, the posterior necrotic zone was absent. The implications of these findings for limb development were discussed.

During the haematogenous spread of tumours, the metastasizing cells must arrest within the blood vessels of the organs they colonize. There is still much debate upon the mechanism of such arrest, whether it is due to mechanical trapping or, more specifically, to adhesion of the tumour cells to the blood vessel wall. This work demonstrates that tumour cells are capable of adhering to blood vessel wall components. According to the hypothesis of specific adhesion, it is thought that metastasizing tumour cells would only come into contact with the vessel wall for a very short time and therefore their adhesion to the vessel wall must be extremely rapid. It has been shown in the past that tumour cells can adhere rapidly to components of the blood vessel wall such as exposed sub-endothelial matrix. Adhesion to endothelial cells was believed to occur at a much slower rate and therefore the involvement of the endothelium during the arrest phase of the metastatic process was thought to be marginal. The experiments carried out during this study show that, in vitro, tumour cells do adhere to the endothelium at a rate comparable to that for isolated components of the sub-endothelial matrix. Furthermore, this work provides some evidence that the molecular basis for such rapid adhesion to the endothelium may be different from the ones involved in the adhesion to known components of the sub-endothelial matrix.