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: 8940452
• 负责人: DAVID A JONES
• 金额: $ 15.31万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-03 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8940452
• 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; Health; Human; Intestines; Link; Measures; Methylation; Modeling; Mus; Mutation; Play; Preventive; Production; Publishing; Regulation; Retinoids; Retinol dehydrogenase; Role; Signal Transduction; System; Testing; Tissues; Tretinoin; Tumor Suppressor Proteins; Work; Zebrafish; genome-wide; intestinal epithelium; novel; prevent; progenitor; stem cells

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（由申请人提供）：APC中的突变被认为通过促进结肠细胞的增殖和阻止其适当分化来启动结肠肿瘤的发展。在上一个资助期，我们有效地利用斑马鱼作为遗传模型系统，以表明视黄酸对肠道发育和分化至关重要，APC通过控制视黄酸的产生来控制肠细胞分化。我们发表的研究表明，APC调节视黄醇脱氢酶的表达，并首次证明了在脊椎动物组织发育中视黄醇脱氢酶的重要作用和动态调节。此外，我们的工作建立了APC和视黄酸在促进肠上皮细胞分化的新作用。作为APC和视黄酸之间的联系，我们证明APC控制转录辅阻遏物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细胞分化。此外，我们已经证明，CtBP和视黄酸的生产失调之前激活Wnt信号。这一观察结果指出，视黄酸的损失作为Apc突变后的起始事件，而不是Wnt的失调。与此模型相一致，我们最近发表的和初步的数据定义了APC，视黄酸和一种新的DNA去甲基化酶系统之间的意想不到的联系，该系统似乎在携带APC突变的斑马鱼中维持肠细胞处于祖细胞样状态。在这种竞争性的更新，我们建立在我们以前的研究，以确定APC，视黄酸和新的DNA去甲基化酶系统在管理肠细胞的命运和分化的机制之间的相互作用。我们推测APC肿瘤抑制因子通过控制视黄酸的产生在正常肠上皮细胞分化中起重要作用。反过来，维甲酸通过抑制一种新的DNA去甲基化酶的活性来调节肠祖细胞内DNA甲基化的重塑。去甲基化酶的下调允许肠道分化所需的关键基因的甲基化依赖性沉默。