PDX-1 IN MAMMALIAN PANCREATIC DEVELOPMENT

描述：（直接取自应用程序）PDX-I基因 （胰腺-十二指肠同源盒基因-以前在非洲爪蟾中称为X1 Hbox 8 （Wright等人，1988）、大鼠中的Idx-1或Stf-1（米勒等人，一九九四年; 伦纳德等人，1994）和小鼠中的Ipf-1（Ohlsson等人，（1994年） 在青蛙和小鼠的内胚层中表达， 十二指肠和胰腺。 众所周知，对于缺失的小鼠， PDX-1基因突变的小鼠无胰腺，并在新生儿时死亡。 PDX-I 因此加入了孤儿同源异型盒基因spx（以前称为Hox-11; Roberts等人，1994年），是一个特定的器官的发展所需要的。 在成熟的鼠胰岛中，PDX-I蛋白特异性地被 在β细胞核中表达。 我们有证据表明PDX-1 是激活胰岛素的转录因子复合物的一部分 转录，通过突变敏感和进化 保守的启动子序列称为Flat-E。 我们提出了一套 解决PDX-I在内胚层区域性炎症中的作用的方法 分化，其区域特异性激活背后的机制， 胰腺/十二指肠区域，以及其在胰岛细胞个体发育中的作用。 我们 将评估PDX-1在早期发育的肺中的错误表达的影响， 上皮和维持其在腺泡（外分泌）细胞中的表达， 通常不表达的。 我们将聘请一位 使用报告基因构建体在体内分析PDX-1基因， 转基因小鼠寻找启动子/增强子模块负责其 正常表达模式。 最后，我们将开始讨论 PDX-1在胰岛细胞分化中的作用 使用Cre-lox P系统进行细胞类型特异性基因切除后的组织，和 在嵌合PDX-1-/-/野生型动物中。

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.