Transcriptional Control of Renal Development by CITED1

CITED1 对肾脏发育的转录控制

• 批准号: 6721397
• 负责人: Mark P. de Caestecker
• 金额: $ 31.55万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721397
• 关键词: Wilms' tumor; cadherins; cell differentiation; developmental genetics; epithelium; gene induction /repression; genetic transcription; histogenesis; immunoaffinity chromatography; kidney; laboratory rat; mammalian embryology; mass spectrometry; mesenchyme; protein structure function; site directed mutagenesis; transcription factor; transfection

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.

描述（申请人提供）：细胞分化的调节 发育对于成人器官的模式和功能至关重要。在 泌尿生殖系统，间充质到上皮转化的异常调节 后肾胚基中的缺陷会导致肾脏先天性缺陷，并且 是肾母细胞中未分化上皮前体细胞扩张的基础 肿瘤。在识别此过程中涉及的因素的屏幕中， 转录辅因子 CITED1/MSGI 在新鲜分离的大鼠中被鉴定 胚芽间充质，在分化后被下调 进入上皮细胞，并在发育中具有显着的胚芽分布 肾和肾母细胞瘤。我们已经证明 CITED 1 的过度表达 阻断培养的后肾​​间质中的上皮形态发生，并且 CITED 1 是一种双功能转录调节因子，可抑制 Wnt-，并且 激活 TGF-β 和骨形态发生蛋白 7 (BMP7) 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 BMP7 信号传导的激活涉及 CITED 1 和 Smad4 之间的功能相互作用。由于 Wnt4 和 BMP7 至关重要 间充质的分化和存活信号，这些发现表明 CITED 1在分化过程中下调的分子机制 后肾胚基可以去抑制 Wnt4 介导的转录反应 并使 Wnt 依赖性上皮形态发生得以发生。在此基础上 我们假设 CITED1 充当双功能转录开关 通过抑制来调节发育中肾脏的上皮形态发生 Wnt/β-连环蛋白和激活 BMP7-Smad4 依赖性转录 回应。我们提出三个具体目标来检验这一假设： 目标 1 和 2 将扩展我们的初步发现，并探索其机制 CITED 1 通过其调节 β-连环蛋白和 Smad4 依赖性转录； 具体目标 3 将利用这些发现来开发特定路径 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。 这些研究形成了定义功能特性的综合方法 CITED 1. 通过这样做，他们将增加我们对 转录控制机制调节分化 后肾胚基，并从长远来看为我们提供了工具 制定靶向策略来干扰异常的胚芽扩张 与肾母细胞瘤有关。