During vertebrate development, precise regulation of cellular proliferation and differentiation is essential for normal organ morphogenesis. Alterations in these processes can lead to neoplastic transformation of a wide range of cell types including the ductular cells and exocrine glands of the pancreas. The coexistence of exocrine and endocrine cells within the pancreas makes it a unique model organ for studying epithelial differentiation and cell fate specification. The pancreatic enzymes and hormones can be readily assayed as markers for exocrine and endocrine differentiation, and molecular markers that characterize different stages of cell fate specification have recently been identified. However, the molecular mechanism that regulates histogenesis and cytodifferentiation of the exocrine pancreas is poorly understood. Continued effort in this area of basic research is important because it is essential to the understanding of normal pancreas development and the early steps of exocrine neoplastic transformation. To identify genes that regulate pancreatic differentiation, a chemical-induced mutagenesis screen in the zebrafish has been performed using exocrine and islet markers. One identified mutant, no exocrine pancreas (nep), lacks immunoreactivity for the pancreatic exocrine enzyme carboxypeptidase A although the exocrine precursor cells are present. As a result, we hypothesize that the nep gene product plays a crucial role in regulating differentiation of the exocrine pancreas and is therefore important for understanding the molecular pathway regulating exocrine pancreas development and possibly pancreas tumorigenesis. In this award application, we propose a strategy to analyze the phenotype of the nep mutant and to identify the actual nep gene. By examining the morphological defect of the nep mutant using histological, ultrastructural and immunohistological techniques, the stage at which exocrine pancreas development is perturbed by the nep mutation can be determined. Testing whether the nep gene acts in a cell-autonomous manner to direct exocrine differentiation will help define the nature of the nep gene function. The chromosomal location of the nep gene will be mapped meiotically using bulked segregant analysis. The region surrounding the nep locus will be delimited by fine resolution meiotic and physical mapping techniques. This analysis will allow us to define the genomic region immediately surrounding the nep locus and ultimately to clone the nep gene. Given the similar development and physiology of the teleost and mammalian pancreas, the genes that direct pancreatic organogenesis are likely to be closely related. Characterization of the nature of the nep gene function and identification of the nep gene will help shed light on the mechanism underlying differentiation of exocrine precursor cells. These data will likely advance our understanding of epithelial differentiation and the development of pancreatic cancer.
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