(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.
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