Research on biological function of ryudocan by knockout mice analysis.

纤维连接蛋白的两个结构域传递局灶粘连形成所需的两种不同但合作的信号。来自细胞结合域的信号由整合素介导，而来自肝素结合域的信号由硫酸肝素蛋白聚糖识别，其中syndecan-4 （ryudocan）被假设参与了局灶性粘连的形成。我们制造了缺乏syndecan-4的小鼠来直接研究它的作用。即使在svndecan-4缺陷小鼠的成纤维细胞中，也形成了局灶性粘连，当在涂有纤维连接蛋白或其细胞结合片段和肝素结合片段的混合物的盖子上培养时，肌动蛋白纤维在局灶性粘连处正常终止。然而，当细胞在细胞结合片段上培养并在培养基中加入肝素结合片段时，与野生型细胞相比，syndecan-4缺失成纤维细胞的局灶粘连形成受到损害。只有当纤维连接蛋白的肝素结合区域的信号以可溶性形式（最有可能是从根尖表面）传递时，syndecan-4才能促进更多的局灶粘连形成。当信号以基底结合形式传递时，其他分子也参与信号接收。研究了syndecan-4在肾脏中的表达及其作用。Syndecan-4在妊娠11.5天的输尿管芽内陷到后肾间质中表达，并一直存在于集合管、远端肾小管、肾小球和肾小管之间的一些毛细血管中，直到肾成熟期。然而，syndecan-4缺乏[Synd4(-/-)]小鼠肾脏器官发生正常。虽然Synd4（-/-）小鼠的大部分肾功能未受到损害，但在Synd4（-/-）小鼠中，k-卡拉胶诱导的肾损伤易感性明显增加。k -卡拉胶严重沉积于Synd4（-/-）小鼠的集管内，引起阻塞性肾病。24只Synd4（-/-）小鼠中有7只在给药后7天内死亡，而24只Synd4（+/+）小鼠无死亡。k-卡拉胶给药后，Syrid4（-/-）小鼠血尿素氮显著高于Synd4（+/+）小鼠，k-卡拉胶与肾髓质膜组分有亲和力，其结合被肝素抑制。因此，syndecan-4可能通过其硫酸肝素起到阻止k-卡拉胶沉积在集管中的作用。少

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 … More 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