PDX-1 IN MAMMALIAN PANCREATIC DEVELOPMENT

PDX-1 在哺乳动物胰腺发育中的作用

• 批准号: 6105437
• 负责人: Christopher V Wright
• 金额: $ 22.99万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105437
• 关键词: cell differentiation; developmental genetics; duodenum; gene expression; gene targeting; genetic enhancer element; genetic promoter element; genetic regulatory element; genetically modified animals; histogenesis; homeobox genes; laboratory mouse; lung; pancreas; pancreatic islets; reporter genes; transcription factor

Description: (Directly taken from the application) The PDX-l gene (pancreas-duodenum homeobox gene - previously called X1Hbox8 in Xenopus (Wright et al., 1988), Idx-l or Stf-l in rat (Miller et al., 1994; Leonard et al., 1994), and Ipf-l in mouse (Ohlsson et al., 1994)) is expressed in the endoderm of frogs and mice in the developing rostral duodenum and pancreas. It is known that mice homozygous for a null mutation of the PDX- l gene have no pancreas and die as neonates. PDX-I thus joins the orphan homeobox gene spx, (previously called Hox-11; Roberts et al., 1994) being required for development of a specific organ. In mature murine pancreatic islets, PDX-I protein is specifically expressed in nuclei of beta cells. We have generated evidence that PDX-1 is part of the transcription factor complex activating insulin transcription, through the mutationally sensitive and evolutionarily conserved promoter sequence termed Flat-E. We propose a set of approaches to address the role of PDX-l in endodermal regional differentiation, the mechanism behind its region-specific activation in the pancreatic/duodenal area, and its role in islet cell ontogeny. We will assess the effects of mis-expressing PDX-1 in early developing lung epithelium and of sustaining its expression in acinar (exocrine) cells, in which it is not normally expressed. We will undertake a promoter analysis of the PDX-1 gene in vivo using reporter gene constructs in transgenic mice to find promoter/enhancer modules responsible for its normal expression pattern. Lastly, we will begin to address the role of PDX-1 in islet differentiation by examining the development of pancreatic tissue after cell type-specific gene excision using Cre-lox P system, and in chimeric PDX-1-/-/wild type animals.

描述：（直接取自应用程序）PDX-L基因 （胰腺duodeNum homeobox基因 - 先前称为X1HBox8在Xenopus中 （Wright等，1988），大鼠IDX-L或STF-L（Miller等，1994; Leonard等，1994）和IPF-L在小鼠中（Ohlsson等，1994）是 在发育中的鼻子中的青蛙和小鼠的内胚层中表达 十二指肠和胰腺。 众所周知，纯合的鼠标为零 PDX-L基因的突变没有胰腺，并且死于新生儿。 pdx-i 因此，加入了孤儿同源基因SPX（先前称为HOX-11； Roberts等，1994）开发特定器官所必需的。 在成熟的鼠胰岛中，PDX-I蛋白特别是 在β细胞的核中表达。 我们已经产生了PDX-1的证据 是转录因子复合物激活胰岛素的一部分 通过突变敏感和进化的转录 保守的启动子序列称为扁平E。 我们提出了一组 解决PDX-L在内皮层次区域中的作用的方法 分化，其区域特异性激活背后的机制 胰腺/十二指肠区域及其在胰岛细胞个体发育中的作用。 我们 将评估早期发育肺中表达误差的PDX-1的影响 上皮并维持其在腺泡（外分）细胞中的表达， 通常不会表达它。 我们将承担促进者 使用报告基因构建体中的PDX-1基因在体内分析 转基因小鼠找到负责其的启动子/增强子模块 正常表达模式。 最后，我们将开始解决 胰岛分化中的PDX-1通过检查胰腺的发展 使用Cre-lox P系统进行细胞类型特异性基因切除后的组织，并 在嵌合PDX-1 - / - /野生型动物中。