Transcriptional Control of Renal Development by CITED1

描述(申请人提供)：细胞分化的调控 在发育过程中对成人器官的构型和功能至关重要。在 泌尿生殖系统间充质向上皮转化的异常调节 在后肾胚芽中会引起肾脏的先天性缺陷， 未分化上皮前体细胞在Wilms病中的扩张 肿瘤。在识别此过程中涉及的因素的屏幕中， 在新分离的大鼠中发现转录辅助因子CITED1/MSGI 胚泡间质在分化过程中表达下调 转化为上皮细胞，并在发育过程中具有显著的胚泡分布。 肾和肾母细胞瘤中。我们已经证明，引用1的过度表达 阻断培养的后肾间充质上皮形态发生 引用1是一个双功能转录调节因子，它抑制Wnt-，和 激活转化生长因子-β和骨形态发生蛋白7(BMP7)依赖的反应。 Wnt信号的抑制与Cred1与Wnt的相互作用有关 β-连环蛋白，而转化生长因子-β和骨形态发生蛋白7信号的激活涉及 引文1和Smad4之间的功能相互作用。因为WNT4和BMP7是关键 这些发现表明，间充质细胞的分化和生存信号 在分化过程中引用1下调的分子机制 后肾胚泡抑制WNT4介导的转录反应 并使依赖Wnt的上皮细胞形态发生。在此基础上 我们假设CITED1发挥双功能转录开关的作用 通过抑制调节发育中的肾脏上皮细胞形态发生 WNT/β-连环蛋白和激活BMP7-Smad4依赖的转录 回应。我们提出了三个具体目标来检验这一假设： 目标1和目标2将扩展我们的初步发现，并探索其机制 通过引用1调节β-连环蛋白和Smad4依赖的转录； 特定目标3将利用这些发现来开发特定被引用的途径1 激动剂和拮抗剂，以确定引用的1的作用和机制 在后肾发育中。 这些研究形成了定义功能属性的综合方法 通过这样做，他们将增加我们对 调控细胞分化的转录调控机制 后肾胚芽，从长远来看，为我们提供了 制定靶向策略以干扰异常的胚泡扩张 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.