| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Two domains of fibronectin deliver two different but cooperative signals required for focal adhesion formation. The signal from the cell-binding domain is mediated by integrins, whereas the signal from the heparin binding domain is recognized by heparan sulfate proteoglycans, of which syndecan-4 (ryudocan) has been hypothesized to be involved in focal adhesion formation. We generated mice deficient in syndecan-4 to study its role directly. Even in fibroblasts from svndecan-4-deficient mice, focal adhesions were formed, and actin fibers terminated normally at focal adhesions when they were cultured on coverslips coated with fibronectin or with a mixture of its cell-binding and heparin binding fragments. However, when the cells were cultured on the cell-binding fragment and the heparin-binding fragment was added to the medium, focal adhesion formation was impaired in the syndecan-4 null fibroblasts as compared with that in wild-type cells. Therefore, syndecan-4 is essential for promoting
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focal adhesion formation only when the signal of the heparin-binding domain of fibronectin is delivered as a soluble form, most probably from the apical surface. When the signal is delivered as a substratum-bound form, other molecule(s) also participate(s) in the signal reception.
The expression and roles of syndecan-4 in the kidney were investigated. Syndecan-4 expression was detected in the ureteric bud invaginating into the metanephric mesenchyme at 11.5 gestational days, and remained in the collecting ducts, distal renal tubules, glomeruli and some capillaries between renal tubules until the mature kidney stage. However, organogenesis of the kidney was normal in syndecan-4-deficient [Synd4(-/-)] mice. Although most of renal functions of Synd4(-/-) mice were not impaired,significant increase of susceptibility to the k-carrageenan-induced renal damage was observed in Synd4(-/-) mice. K-Carrageenan was deposited severely in the collecting ducts of Synd4(-/-) mice and caused obstructive nephropathy. Leading to death of 7 of 24 Synd4(-/-) mice within 7 days after administration, whereas none of 24 Synd4(+/+) mice died. After the administration ofk carrageenan, blood urea nitrogen of Syrid4(-/-) mice was significantly higher than that of Synd4(+/+) mice, k-Carrageenan had affinity to the membrane fraction derived from the medulla of the kidney, and its binding was inhibited by heparin. Thus, syndecan-4 may function to prevent k-carrageenan deposition in the collecting ducts via its heparan sulfates. Less
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