Molecular Regulation of Pancreas Cell Fate Determination

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DESCRIPTION (provided by applicant): Most organs contain a variety differentiated cell types that are derived from a pool of uncommitted progenitor cells. How the correct number of different cell types are specified - the process of cell fate determination - is a central question in organogenesis. This problem applies to the pancreas, which contains exocrine cells, which produce digestive enzymes, and endocrine cells, which make pancreatic hormones, including insulin. The goal of this project is to understand the mechanism by which pancreatic progenitor cells are instructed to become exocrine or endocrine cells, through the process of cell fate determination. Previous work has suggested that Notch - a complex receptor signaling pathway that is widely used during embryogenesis to control differentiation - plays an important role determining pancreatic cell fate. This proposal aims to answer three questions. First, can manipulation of the Notch signal lead to changes in the proportion of exocrine and endocrine cells that form? This will be addressed by mis-expressing activators and inhibitors of the Notch pathway in transgenic mice to determine the effect on cell fate. Second, how are Notch signals regulated in the pancreas? This will be addressed by characterizing the expression of elements of the Notch pathway when known mediators of endocrine differentiation are expressed in chick embryos. Third, what is the function of the mouse Sel-1l protein, a negative regulator of Notch in C. elegans which is expressed in the mammalian pancreas. This will be addressed by inactivating the Sel-1l gene. Clarifying the mechanism by which cell fate decisions are made in the pancreas will enhance the general understanding of the process of organogenesis. Many degenerative diseases, including pancreatic insufficiency and type I diabetes, result from the loss important differentiated cell types. Practically, an understanding of the mechanisms by which the organism specifies such cell types may confer the ability to experimentally manipulate tissues for therapy.