Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6.
Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6.
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DOI：
10.1093/hmg/ddp434
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发表时间：
2009-12-15
影响因子：
3.5
通讯作者：
Saunier S
中科院分区：
文献类型：
--
作者：
Delous M;Hellman NE;Gaudé HM;Silbermann F;Le Bivic A;Salomon R;Antignac C;Saunier S
肾单位综合征(NPH)是一种常染色体隐性遗传性疾病，以肾纤维化、肾小管基底膜破裂和皮髓囊肿形成为特征，最终导致终末期肾功能衰竭。这种疾病是由NPHP1-9基因突变引起的，该基因编码肾囊蛋白，定位于细胞-细胞连接和中心体/初级纤毛的蛋白质。在这里，我们发现在细胞极化过程中肾囊藻毒素mRNA的表达显著增加，当生长在三维胶原基质中时，shRNA介导的NPHP1或NPHP4在MDCK细胞中的敲除导致延迟紧密连接(TJ)的形成、异常纤毛的形成和无序的多腔结构。其中一些表型与TJ蛋白PALS1或PAR3缺失的细胞的表型相似，有趣的是，我们证明了这些肾囊蛋白与PALS1及其伴侣PATJ和PAR6之间的物理相互作用，并显示它们在人肾小管中的部分共定位。综上所述，这些结果表明，肾囊素在上皮细胞组织中起着重要的作用，提示了NPH体内组织病理学特征可能的发展机制。
Nephronophthisis (NPH) is an autosomal recessive disorder characterized by renal fibrosis, tubular basement membrane disruption and corticomedullary cyst formation leading to end-stage renal failure. The disease is caused by mutations in NPHP1-9 genes, which encode the nephrocystins, proteins localized to cell–cell junctions and centrosome/primary cilia. Here, we show that nephrocystin mRNA expression is dramatically increased during cell polarization, and shRNA-mediated knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed tight junction (TJ) formation, abnormal cilia formation and disorganized multi-lumen structures when grown in a three-dimensional collagen matrix. Some of these phenotypes are similar to those reported for cells depleted of the TJ proteins PALS1 or Par3, and interestingly, we demonstrate a physical interaction between these nephrocystins and PALS1 as well as their partners PATJ and Par6 and show their partial co-localization in human renal tubules. Taken together, these results demonstrate that the nephrocystins play an essential role in epithelial cell organization, suggesting a plausible mechanism by which the in vivo histopathologic features of NPH might develop.
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Otto, EA;Schermer, B;Hildebrandt, F
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