Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions.
Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions.
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DOI：
10.1371/journal.pone.0129346
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lipschutz JH
中科院分区：
文献类型：
--
作者：
Fogelgren B;Polgar N;Lui VH;Lee AJ;Tamashiro KK;Napoli JA;Walton CB;Zuo X;Lipschutz JH
大多数先天性梗阻性肾病是输尿管肾盂连接部梗阻的结果，尽管其发病率很高，但我们对其病因和遗传模式缺乏了解。八蛋白胞囊复合体在多种细胞类型中调节细胞内囊泡的极化胞吐。在这里，我们报道了一种条件基因敲除小鼠的产生，Sec10是胞囊的中心成分，它是任何胞囊基因的第一个条件等位基因。Ksp1.3-Cre小鼠输尿管芽细胞中Sec10的失活导致新生儿严重的双侧肾积水和完全性无尿，死亡发生在出生后6-14小时。Sec10FL/FL；KSP-CRE胚胎在E17.5~E18.5之间由于尿路上皮的退化和周围间充质细胞的过度生长而出现输尿管肾盂连接部梗阻。排在尿路的尿路上皮细胞层必须保持疏水的管腔屏障，同时保持高度伸展能力。这种屏障在很大程度上是通过产生尿路蛋白来建立的，这些蛋白被运输到根尖表面以建立大的斑块。在E16.5，Sec10FL/FL；KSP-CRE输尿管和盆腔尿路上皮显示Uroplakin-3蛋白在管腔表面减少，E17.5完全缺乏Uroplakin-3。受影响的UPJ处的尿路上皮显示不规则的屏障，使平滑肌层暴露在尿液中，这表明这可能会触发周围的间充质细胞过度生长管腔。这一新的小鼠模型的研究结果表明，Sec10对输尿管尿路上皮的发育至关重要，并提供了实验证据，表明这种尿路上皮屏障的失败可能导致人类先天性尿路梗阻。
Most cases of congenital obstructive nephropathy are the result of ureteropelvic junction obstructions, and despite their high prevalence, we have a poor understanding of their etiology and scarcity of genetic models. The eight-protein exocyst complex regulates polarized exocytosis of intracellular vesicles in a large variety of cell types. Here we report generation of a conditional knockout mouse for Sec10, a central component of the exocyst, which is the first conditional allele for any exocyst gene. Inactivation of Sec10 in ureteric bud-derived cells using Ksp1.3-Cre mice resulted in severe bilateral hydronephrosis and complete anuria in newborns, with death occurring 6–14 hours after birth. Sec10FL/FL;Ksp-Cre embryos developed ureteropelvic junction obstructions between E17.5 and E18.5 as a result of degeneration of the urothelium and subsequent overgrowth by surrounding mesenchymal cells. The urothelial cell layer that lines the urinary tract must maintain a hydrophobic luminal barrier again urine while remaining highly stretchable. This barrier is largely established by production of uroplakin proteins that are transported to the apical surface to establish large plaques. By E16.5, Sec10FL/FL;Ksp-Cre ureter and pelvic urothelium showed decreased uroplakin-3 protein at the luminal surface, and complete absence of uroplakin-3 by E17.5. Affected urothelium at the UPJ showed irregular barriers that exposed the smooth muscle layer to urine, suggesting this may trigger the surrounding mesenchymal cells to overgrow the lumen. Findings from this novel mouse model show Sec10 is critical for the development of the urothelium in ureters, and provides experimental evidence that failure of this urothelial barrier may contribute to human congenital urinary tract obstructions.
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影响因子：
3.7
作者：
Haraguchi R;Matsumaru D;Nakagata N;Miyagawa S;Suzuki K;Kitazawa S;Yamada G
通讯作者：
Yamada G
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
3.3
作者：
Hu, CCA;Liang, FX;Sun, TT
通讯作者：
Sun, TT
DOI：
10.1093/bfgp/elm022
发表时间：
2007-09-01
期刊：
Briefings in Functional Genomics & Proteomics
影响因子：
--
作者：
Friedel, Roland H.;Seisenberger, Claudia;Wurst, Wolfgang
通讯作者：
Wurst, Wolfgang
影响因子：
30.3
作者：
Guichard A;Cruz-Moreno B;Aguilar B;van Sorge NM;Kuang J;Kurkciyan AA;Wang Z;Hang S;Pineton de Chambrun GP;McCole DF;Watnick P;Nizet V;Bier E
通讯作者：
Bier E