APC and Retinoids in Zebrafish Enterocyte Development

斑马鱼肠细胞发育中的 APC 和类维生素A

• 批准号: 8403795
• 负责人: DAVID A JONES
• 金额: $ 26.58万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403795
• 关键词: Adult; Biological Models; C-terminal binding protein; Cell Differentiation process; Cells; Clinical; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; DNA; DNA Methylation; Data; Development; Down-Regulation; Enterocytes; Enzymes; Event; Funding; Genes; Genetic; Genetic Models; Goals; Human; Intestines; Link; Measures; Methylation; Modeling; Mus; Mutation; Play; Preventive; Production; Publishing; Regulation; Retinoids; Retinol dehydrogenase; Role; Signal Transduction; Stem cells; System; Testing; Tissues; Tretinoin; Tumor Suppressor Proteins; Work; Zebrafish; genome-wide; intestinal epithelium; novel; prevent; progenitor; public health relevance

DESCRIPTION (provided by applicant): Mutations in APC are thought to initiate colon tumor development by promoting proliferation and preventing proper differentiation of colonocytes. In the previous funding period, we effectively employed zebrafish as a genetic model system to show that retinoic acid is essential for intestinal development and differentiation and that APC controls intestinal cell differentiation by controlling the production of retinoic acid. Our published studies indicate that APC regulates the expression of retinol dehydrogenases and were the first to demonstrate an essential role for, and dynamic regulation of, retinol dehydrogenases in vertebrate tissue development. Moreover, our work has established novel roles for APC and retinoic acid in promoting enterocyte differentiation. As a link between APC and retinoic acid, we demonstrated that APC controls the stability of the transcriptional co-repressor, C-terminal binding protein (CtBP) which can directly repress retinol dehydrogenases and intestinal cell differentiation. Further, we have demonstrated that dysregulation of CtBP and retinoic acid production precedes activation of Wnt signaling. This observation points to loss of retinoic acid as the initiating event following Apc mutation rather than dysregulation of Wnt. Consistent with this model, our most recent published and preliminary data define an unexpected connection between APC, retinoic acid and a novel DNA demethylase system that appears to maintain intestinal cells in a progenitor-like state in zebrafish harboring Apc mutations. In this competitive renewal, we build upon our previous studies to define the mechanistic interplay between Apc, retinoic acid and the novel DNA demethylase system in governing intestinal cell fate and differentiation. We hypothesize that the APC tumor suppressor plays an essential role in normal enterocyte differentiation by controlling the production of retinoic acid. Retinoic acid, in turn, regulates remodeling of DNA methylation within intestinal progenitor cells by suppressing the activity of a novel DNA demethylase. Downregulation of the demethylase allows methylation-dependent silencing of key genes required for intestinal differentiation.

描述(申请人提供)：APC的突变被认为通过促进增殖和阻止结肠癌细胞的适当分化而启动结肠癌的发展。在之前的资助期间，我们有效地使用斑马鱼作为遗传模型系统，以表明维甲酸对肠道发育和分化是必不可少的，APC通过控制维甲酸的产生来控制肠道细胞分化。我们已发表的研究表明，APC调节视黄醇脱氢酶的表达，并首次证明了视黄醇脱氢酶在脊椎动物组织发育中的重要作用和动态调节。此外，我们的工作确立了APC和维甲酸在促进肠细胞分化中的新作用。作为APC和维甲酸之间的纽带，我们证明了APC控制着转录共抑制因子C末端结合蛋白(CtBP)的稳定性，CtBP可以直接抑制视黄醇脱氢酶和肠道细胞分化。此外，我们还证明了CtBP和维甲酸产生的失调先于Wnt信号的激活。这一观察结果表明，维甲酸的丢失是APC突变后的启动事件，而不是Wnt的调节失调。与这一模型一致，我们最新发表的和初步的数据定义了APC、维甲酸和一个新的DNA去甲基酶系统之间意想不到的联系，该系统似乎在携带APC突变的斑马鱼中维持肠道细胞处于祖细胞状态。在这一竞争性更新中，我们在以前研究的基础上，确定了APC、维甲酸和新的DNA去甲基酶系统在控制肠道细胞命运和分化方面的机制相互作用。我们推测，APC肿瘤抑制因子通过控制维甲酸的产生，在正常的肠细胞分化中发挥重要作用。维甲酸反过来通过抑制一种新的DNA去甲基酶的活性来调节肠道前体细胞内DNA甲基化的重塑。去甲基酶的下调允许甲基化依赖的沉默肠道分化所需的关键基因。