Program in Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Division of Nephrology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Am J Pathol. 2014 May;184(5):1395-410. doi: 10.1016/j.ajpath.2014.01.018. Epub 2014 Mar 15.
Renal dysplasia, a developmental disorder characterized by defective ureteric branching morphogenesis and nephrogenesis, ranks as one of the major causes of renal failure among the pediatric population. Herein, we demonstrate that the levels of activated β-catenin are elevated in the nuclei of ureteric, stromal, and mesenchymal cells within dysplastic human kidney tissue. By using a conditional mouse model of mesenchymal β-catenin overexpression, we identify two novel signaling pathways mediated by β-catenin in the development of renal dysplasia. First, the overexpression of β-catenin within the metanephric mesenchyme leads to ectopic and disorganized branching morphogenesis caused by β-catenin directly binding Tcf/lef consensus binding sites in the Gdnf promoter and up-regulating Gdnf transcription. Second, β-catenin overexpression in the metanephric mesenchyme leads to elevated levels of transcriptionally active β-catenin in the ureteric epithelium. Interestingly, this increase of β-catenin-mediated transcription results from a novel Ret/β-catenin signaling pathway. Consistent with these findings, analysis of human dysplastic renal tissue demonstrates that undifferentiated mesenchymal cells expressing high levels of β-catenin also express increased GDNF. Furthermore, dysplastic ureteric tubules that were surrounded by high levels of GDNF also exhibited increased levels of activated β-catenin. Together, these data support a model in which the elevation of β-catenin in the metanephric mesenchyme results in cell-autonomous and non-cell-autonomous events that lead to the genesis of renal dysplasia.
肾发育不良是一种以输尿管分支形态发生和肾发生缺陷为特征的发育障碍，是小儿肾衰竭的主要原因之一。本文中，我们发现活性β-catenin 在人肾发育不良组织的输尿管、基质和间充质细胞的核中升高。通过使用间充质β-catenin 过表达的条件性小鼠模型，我们确定了β-catenin 在肾发育不良发生过程中两条新的信号通路。首先，β-catenin 在肾间充质中的过表达导致 Gdnf 启动子中β-catenin 直接结合 Tcf/lef 共识结合位点和上调 Gdnf 转录引起的异位和紊乱的分支形态发生。其次，β-catenin 在肾间充质中的过表达导致输尿管上皮中转录活性β-catenin 的水平升高。有趣的是，这种β-catenin 介导的转录增加来自于一个新的 Ret/β-catenin 信号通路。与这些发现一致，对人发育不良肾组织的分析表明，表达高水平β-catenin 的未分化间充质细胞也表达增加的 GDNF。此外，被高水平 GDNF 包围的发育不良的输尿管小管也表现出激活的β-catenin 水平增加。总之，这些数据支持了这样一种模型，即肾间充质中β-catenin 的升高导致了导致肾发育不良发生的细胞自主和非细胞自主事件。
