Transcriptional Control of Renal Development by CITED1

描述（由申请人提供）：细胞分化的调节 对成年器官的形成和功能至关重要。在 泌尿生殖系统，间充质向上皮转化的异常调节 在后肾芽基中引起肾的先天性缺陷，并且 是Wilms'细胞中未分化上皮前体细胞扩张的基础。 肿瘤的在识别此过程中涉及的因素的屏幕中， 转录辅因子CITED 1/MSGI，在新鲜分离的大鼠中鉴定 胚间充质，显示在分化后下调 进入上皮细胞，并在发育中具有显著的胚基分布。 肾和肾母细胞瘤我们已经证明，过度表达CITED 1 阻断培养的后肾间充质中的上皮形态发生， CITED 1是一种双功能转录调节因子，抑制Wnt-， 激活TGF-β和骨形态发生蛋白7（BMP 7）依赖性反应。 Wnt-信号传导的抑制与CITED 1与 β-连环蛋白，而TGF-β和BMP 7信号的激活涉及 CITED 1和Smad 4之间的功能相互作用。由于Wnt 4和BMP 7至关重要 间充质细胞的分化和存活信号，这些发现表明 一种分子机制，其中下调CITED 1在分化 后肾芽基可以解除Wnt 4介导的转录反应 并使Wnt依赖的上皮形态发生发生。在此基础上 我们假设CITED 1是一个双功能转录开关， 在发育中的肾脏中通过抑制 Wnt/β-连环蛋白-和激活BMP 7-Smad 4-依赖性转录 应答我们提出了三个具体的目标来检验这一假设： 目的1和2将扩展我们的初步研究结果，并探讨其机制 CITED 1通过其调节β-连环蛋白和Smad 4依赖的转录; Specific Aim 3将利用这些发现开发途径特异性CITED 1 激动剂和拮抗剂，以确定CITED 1的作用和机制 在后肾发育中的作用 这些研究形成了一个综合的方法来定义功能特性 引用1。这样做，他们将增加我们对 转录调控机制调节分化的 后肾芽基，并在长期内为我们提供了工具， 开发靶向策略以干扰异常胚体扩展 与肾母细胞瘤有关

DESCRIPTION (provided by applicant):The regulation of cellular differentiation in development is critical for patterning and function of adult organs. In the urogenital system, abnormal regulation of mesenchyme to epithelial transition in the metanephric blastema gives rise to congenital defects in the kidney, and underlies the expansion of undifferentiated epithelial precursors in Wilms' tumors. In a screen to identify factors involved in this process, the transcriptional co-factor CITED1/MSGI, was identified in freshly isolated rat blastemal mesenchymes, shown to be down-regulated following differentiation into epithelia, and to have a striking blastemal distribution in the developing kidney and in Wilms' tumors. We have shown that over-expression of CITED 1 blocks epithelial morphogenesis in cultured metanephric mesenchymes, and that CITED 1 is a bifunctional transcriptional regulator that represses Wnt-, and activates TGF-beta and Bone Morphogenetic Protein 7 (BMP7)-dependent responses. Suppression of Wnt-signaling is associated with an interaction of CITED 1 with beta-catenin, while activation of TGF-beta and BMP7-signaling involves a functional interaction between CITED 1 and Smad4. As Wnt4 and BMP7 are critical differentiation and survival signals for the mesenchyme, these findings suggest a molecular mechanism whereby down-regulation of CITED 1 in the differentiating metanephric blastema could de-repress Wnt4-mediated transcriptional responses and enable Wnt-dependent epithelial morphogenesis to take place. On this basis we hypothesize that CITED1 acts a bi-functional transcriptional switch that regulates epithelial morphogenesis in the developing kidney by repressing Wnt/beta-catenin- and activating BMP7-Smad4-dependent transcriptional responses. We propose three specific aims to test this hypothesis: Specific Aims 1 and 2 will extend our preliminary findings, and explore the mechanisms by which CITED 1 regulates beta-catenin and Smad4-dependent transcription; Specific Aim 3 will exploit these findings to develop pathway specific CITED 1 agonists and antagonists in order to define the role and mechanism of CITED 1 in metanephric development. These studies form an integrated approach to define the functional properties of CITED 1. In so doing, they will increase our understanding of the transcriptional control mechanisms regulating differentiation of the metanephric blastema, and in the longer term provide us with the tools to develop targeting strategies to interfere with aberrant blastemal expansion associated with Wilms' tumors.