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News and Publications
Integrin Collagen Receptors
H.A.R. Gardner, A. Pozzi
We use gene-targeting technology to study transmembrane integrin receptors for collagens. Three integrin receptors bind collagen:  1ß1, 2ß1, and 3ß1. Several years ago, we created mice that lack the gene for 1ß1. These animals survive but have a variety of subtle defects. For example, some tissues have a defect in proliferation normally signaled by collagen, because 1ß1 is the only collagen receptor capable of activating the machinery of the cell cycle. This finding has potential implications for T-cell survival in inflammatory and autoimmune diseases and also in angiogenesis, in which 1ß1 is abundant on small blood vessels. We are using several in vivo models to explore T-cell survival and angiogenesis in 1 null mice.
A second major dysfunction in 1 null mice is in collagen metabolism. These animals have a greatly increased rate of collagen synthesis, which is partly compensated for in vivo by increases in collagen breakdown. We are exploring the hypothesis that 1ß1normally provides negative feedback regulation of collagen synthesis. We found that fibroblasts from 1ß1 null mice are hypersensitive ex vivo to the profibrotic effects of transforming growth factor-ß, probably because of the absence of the 1ß1 feedback loop. This effect may be important in some fibrotic diseases, especially scleroderma, in which expression of 1ß1 is reduced.
The second collagen-binding integrin, 2ß1, is mostly expressed on epithelial cells. We have created a targeted null mutation for this integrin. In stark contrast to 1 null mice, 2 null mice die in utero approximately in mid gestation, at an age similar to that of animals with a deletion in the collagen I gene itself. Thus, the interaction between 2ß1 and collagen appears to be essential for embryonic development.
PUBLICATIONS
Pozzi, A., Wary, K., Giancotti, F.G., Gardner, H.A.R. Integrin 1ß1 mediates a unique collagen-dependent proliferation pathway in vivo. J. Cell Biol. 142:587, 1998.
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