Characterization of the Wilms tumor suppressor gene X (WTX) in tumorigenesis and normal kidney development of the mouse

肾母细胞瘤是小儿最常见的肾癌，与肾器官发生密切相关。发现与肾发育相关的各种基因在肾母细胞瘤中不适当地失活，例如WT 1，而其他基因似乎被激活，例如CTNNB 1，编码Wnt信号通路的组分;然而，对于大多数肾母细胞瘤，没有检测到一致的特异性畸变。最近，通过在30%的肾母细胞瘤中发现一种新的失活基因，该基因位于X染色体上，命名为WTX，可以克服这一障碍。本项目的目的是研究小鼠中灭活的WTX，以确定和表征其在肾发生过程中的影响。为此，我将使用条件性WTX敲除小鼠，其允许WTX的时间和组织特异性表达，并且还将允许我建立基于WTX功能丧失的体内Wilms肿瘤模型。我将使用这种遗传工具来显示WTX在这种儿科癌症以及正常肾发生中的显著相关性。总之，WTX的分析将允许关于其生物学功能、涉及的分子机制和途径以及其对肾前体细胞中的致瘤事件的贡献的结论。

Wilms tumor is the most common pediatric kidney cancer and closely associated with renal organogenesis. Various genes associated with kidney development are found inappropriately inactivated in Wilms tumor, e.g. WT1, while others appear activated, such as CTNNB1, encoding a component of the Wnt signaling pathway; however, for the majority of Wilms tumor, no consistently specific aberrations have been detected. Recently, this obstacle could be overcome through the discovery of a novel inactivated gene in 30% of Wilms tumor, which is located on the X chromosome and named WTX. The aim of this project is to study inactivated WTX in the mouse to identify and characterize its influence during nephrogenesis. For this purpose, I will use a conditional WTX knockout mouse, which allows temporal and tissue-specific expression of WTX, and also will allow me to establish an in vivo Wilms tumor model based on WTX loss-of-function. I will use this genetic tool to show the significant relevance of WTX in this pediatric cancer as well as in normal nephrogenesis. In summary, the analysis of WTX will allow conclusions about its biological function, involved molecular mechanisms and pathways, as well as its contribution to tumorigenic events in renal precursor cells.