PDX-1 IN MAMMALIAN PANCREATIC DEVELOPMENT

描述：(直接取自申请)pdx-L基因 (胰腺-十二指肠同源盒基因-以前在非洲爪哇被称为X1Hbox8 (Wright等人，1988年)，Idx-L或Stf-L(Miller等人，1994年； Leonard等人，1994年)和IPF-L(Ohlsson等人，1994)是 在发育期青蛙和小鼠内胚层中的表达 十二指肠和胰腺。已知纯合子为空的小鼠 突变的pdx-L基因没有胰腺，会在新生儿时期死亡。PDX-I 这样就加入了孤儿同源框基因SPx，(以前称为Hox-11； Roberts等人，1994)是发展特定器官所必需的。 在成熟的小鼠胰岛中，PDX-I蛋白是特异性的 在β细胞的细胞核中表达。我们已经产生了证据表明PDX-1 是激活胰岛素的转录因子复合体的一部分 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 PDX-L对内皮局灶性病变作用的探讨 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 将评估错误表达PDX-1在早期发育肺中的作用 上皮细胞及其在腺泡(外分泌)细胞中的表达， 它通常不会在其中表达。我们将聘请一名推广人 用报告基因构建法在体内分析PDX-1基因 转基因小鼠寻找与其相关的启动子/增强子模块 正常的表情模式。最后，我们将开始讨论 PDX-1在胰岛分化中的作用 使用Cre-lox P系统切除细胞类型特异性基因后的组织，以及 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.