The development of the mammalian pancreas represents an attractive model system to study the molecular signals that direct the commitment and differentiation of epithelial cells along different cell lineages. The pancreas consists of two distinct tissue types which carry out different essential functions. The endocrine pancreas regulates blood sugar levels by secreting glucagon or insulin whereas the exocrine pancreas secretes digestive enzymes into the duodenal part of the small intestine. Although many of the transcription factors responsible for endocrine pancreas formation have been identified and extensively studied, the molecular regulatory circuits that control the establishment and maintenance of the exocrine pancreas are just beginning to be elucidated. Towards a goal of identifying key transcriptional regulators of pancreatic development and function, a novel basic helix-loop-helix (bHLH) transcription factor (Mistl) recently was identified that accumulates to high levels in pancreatic exocrine cells. Mistl gene expression is initially detected at mouse embryonic day E10.5 in the developing pancreas and remains expressed to high levels in the acinar cells of the adult. Although the Mistl nuclear protein is capable of binding to specific DNA targets as a homodimer or as a heterodimer with other bHLH transcription factors, it lacks a typical transcription activation domain and instead can serve as a transcriptional repressor in some experimental systems. At this time, a true role for Mistl activity in pancreatic function has not been established, although its expression pattern and DNA binding capabilities suggest that Mistl likely serves as a key regulator of exocrine pancreas gene activity. In order to characterize further the biochemical properties of the Mistl protein and the role of Mistl in pancreatic development, studies are proposed to (1) examine the activity of Mistl using a pancreatic cell line model system, (2) identify pancreas-specific Mistl protein binding partners and (3) utilize mouse genetic approaches to create Mistl homozygous null mice and to identify Mistl target genes. In addition, targeted replacement of the Mistl gene with an activated K-ras allele will be performed to generate novel pancreatic cancer models. A complete characterization of Mistl activity in exocrine pancreatic cells will add critical new information regarding normal pancreatic development and function and may provide future strategies for combating several key human diseases, including acute pancreatitis and pancreatic cancer.
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