Tsc1 ablation in Prx1 and Osterix lineages causes renal cystogenesis in mouse
Tsc1 ablation in Prx1 and Osterix lineages causes renal cystogenesis in mouse
复制标题
Prx1 和 Osterix 谱系中的 Tsc1 消除导致小鼠肾囊肿发生
DOI：
10.1038/s41598-018-37139-9
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发表时间：
2019-01-29
影响因子：
4.6
通讯作者：
Li，Jing
中科院分区：
文献类型：
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作者：
Wu，Zhixiang;Wu，Hongguang;Li，Jing
结节性硬化症 (TSC) 是由 TSC1 或 TSC2 突变引起的，它们编码 mTOR 信号通路的负调节因子。与 TSC 相关的肾脏异常包括血管平滑肌脂肪瘤、囊肿和肾细胞癌。在这里，我们报告使用间充质干细胞-成骨细胞谱系标记物特异性消融 Tsc1 诱导小鼠的囊肿发生。使用 Rosa-tdTomato 小鼠，我们发现 Prx1 或 Dermo1 标记的细胞存在于包括肾小球在内的肾单位中，但它们没有被足细胞、系膜细胞、内皮细胞或近端或亨利小管细胞环的标记物染色，而已知 Osx 可以标记肾小管细胞。 Prx1谱系细胞中的Tsc1缺陷导致轻度囊肿的形成，仅对Tamm-Horsfall蛋白（THP）（Henle标记物的环）呈阳性，而Osx谱系细胞中的Tsc1缺陷导致囊肿的形成对Villin（近端肾小管细胞标记物）呈阳性。另一方面，Dermo1 谱系中的 Tsc1 缺陷并没有在肾脏中产生可检测到的表型变化。 Prx1-Cre 中囊肿形成； Tsc1f/f 和 Osx-Cre； Tsc1f/f 小鼠与受影响组织中增殖和凋亡细胞的增加有关，并且在很大程度上被雷帕霉素抑制。这些结果表明 Prx1 和 Osx 谱系细胞可能有助于 TSC 患者的肾囊肿发生。
Tuberous Sclerosis Complex (TSC) is caused by mutations in TSC1 or TSC2, which encode negative regulators of the mTOR signaling pathway. The renal abnormalities associated with TSC include angiomyolipoma, cysts, and renal cell carcinoma. Here we report that specific ablation of Tsc1 using the mesenchymal stem cell-osteoblast lineage markers induced cystogenesis in mice. Using Rosa-tdTomato mice, we found that Prx1- or Dermo1-labeled cells were present in the nephron including glomerulus but they were not stained by markers for podocytes, mesangial cells, endothelial cells, or proximal or loop of Henle tubular cells, while Osx is known to label tubular cells. Tsc1 deficiency in Prx1 lineage cells caused development of mild cysts that were positive only for Tamm-Horsfall protein (THP), a loop of Henle marker, while Tsc1 deficiency in Osx lineage cells caused development of cysts that were positive for Villin, a proximal tubular cell marker. On the other hand, Tsc1 deficiency in the Dermo1 lineage did not produce detectable phenotypical changes in the kidney. Cyst formation in Prx1-Cre; Tsc1f/f and Osx-Cre; Tsc1f/f mice were associated with increase in both proliferative and apoptotic cells in the affected tissue and were largely suppressed by rapamycin. These results suggest that Prx1 and Osx lineages cells may contribute to renal cystogenesis in TSC patients.