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Title: The regulation of Fibronectin matrix assembly by Tenascin-C
Author: To, Wing Sum
ISNI:       0000 0004 2682 2803
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Fibronectin (FN) is a ubiquitous component of the extracellular matrix (ECM). Its assembly into 3D fibrillar matrices is essential during development and tissue repair to maintain tissue architecture and provide environmental signals to cells. However, FN deposition must be tightly regulated as excessive assembly is a major hallmark of fibrotic diseases and cancer. Tenascin-C (TN-C) is a large, multi-domain ECM glycoprotein that co-localizes with newly synthesized FN fibrils in vivo during development, wound repair and tumorigenesis. However, it is not known precisely how FN and TN-C interact within the ECM, or whether their interaction has any functional relevance. I have demonstrated that distinct domains of TN-C inhibit FN matrix assembly by fibroblasts, whereas full length TN-C has no effect. I have identified regions within TN-C domains that are essential for binding to fibrillar FN, but not to soluble FN, and mapped where they interact within the FN molecule. I have found that domains containing these regions interfere with inter-molecular FN-FN interactions during fibrillogenesis. I also identified other TN-C domains that interfered with FN matrix assembly by FNindependent mechanisms. I demonstrated that one of these TN-C domains was internalized by fibroblasts causing morphological changes that may interfere with cytoskeleton organization or cell surface receptor availability to prevent the maintenance of a fibrillar FN matrix at the cell surface. Recently emerging evidence indicates that deposition of FN by epithelial and endothelial cells is absolutely vital for tubulogenesis and the formation of new blood vessels. Without this scaffold, the cells fail to generate sufficient tensional force required for the morphogenesis and migration essential for tubule formation. I have shown that specific domains of TN-C can inhibit tubulogenesis by epithelial cells within a 3D collagen matrix and may also affect angiogenesis of endothelial cells within a 3D collagen matrix environment. These data suggest that proteolysis of TN-C during tissue remodelling may create fragments that act to limit FN matrix assembly. Persistent TN-C expression during fibrosis and tumour growth may contribute to uncontrolled FN deposition and angiogenesis during disease progression.
Supervisor: Midwood, Kim Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral