Role of cdx genes and RA in regionalizing the endoderm

cdx 基因和 RA 在内胚层区域化中的作用

• 批准号: 7249400
• 负责人: MARY D KINKEL
• 金额: $ 5.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249400
• 关键词: Biological Models; Cell Transplantation; Cells; Development; Ectoderm; Embryo; Endoderm; Exocrine pancreas; Family; Gastrointestinal tract structure; Gene Family; Genes; Goals; Hepatocyte; Islets of Langerhans; Lead; Liver; Localized; Mesoderm; Midgut; Molecular; Mus; Organ; Pancreas; Pattern; Play; Population; Positioning Attribute; Regulation; Research; Role; Signal Transduction; Skeleton; Small Intestines; System; Testing; To specify; Tretinoin; Vertebrates; Work; Zebrafish; base; gene function; intestinal epithelium; loss of function; mutant; precursor cell; research study; transcription factor

DESCRIPTION (provided by applicant): The broad objective of this proposal is to examine the roles of cdx genes and retinoic acid (RA) in regionalizing the zebrafish midgut, with particular emphasis on the pancreas and liver. RA signaling has been shown to be necessary to specify the zebrafish pancreas and liver, and the role of RA in pancreas development is conserved across vertebrates. The mechanism whereby RA functions in this context is unknown. Studies on mesoderm and ectoderm have suggested that RA functions upstream of Cdx transcription factors, which in turn signal to downstream hox genes. My preliminary experiments have established that cdx4 is required for normal pancreas localization along the digestive tract. My general strategy is to test the working hypothesis that pancreas localization relies on integrating anteriorally-derived RA signals and posteriorally-derived Cdx signals. I will investigate the roles of cdx4 and cdx2 in regionalizing the endoderm using loss-of-function approaches. Since Cdx genes have been shown to function synergistically in other systems, I will investigate whether cdx4 and cdx2 function synergistically during endoderm patterning. Using cell transplantation I will generate chimeric embryos to determine whether cdx4 influences pancreatic fate cell-autonomously versus non-cell-autonomously. Finally, I will investigate the role of RA signaling in regulating Cdx genes utilizing loss-of-function approaches as well as treatment with exogenous RA.

描述（由申请人提供）： 该建议的主要目的是研究cdx基因和视黄酸（RA）在斑马鱼中肠区域化中的作用，特别强调胰腺和肝脏。RA信号已被证明是必要的，以指定斑马鱼胰腺和肝脏，和RA在胰腺发育中的作用是保守的脊椎动物。RA在这种情况下发挥作用的机制尚不清楚。对中胚层和外胚层的研究表明，RA在Cdx转录因子的上游起作用，Cdx转录因子反过来向下游hox基因发出信号。我的初步实验已经证实cdx 4是正常胰腺定位于沿着消化道所必需的。我的总体策略是测试胰腺定位依赖于整合前衍生的RA信号和后衍生的Cdx信号的工作假设。我将研究cdx4和cdx2的作用，在区域化内胚层功能丧失的方法。由于Cdx基因已被证明在其他系统中发挥协同作用，我将研究cdx4和cdx2是否协同作用，在内胚层图案。利用细胞移植，我将产生嵌合体胚胎，以确定cdx4是否影响胰腺命运细胞自主与非细胞自主。最后，我将研究RA信号在调节Cdx基因利用功能丧失的方法，以及与外源性RA治疗的作用。