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Charles Murtaugh

Assistant Professor of Human Genetics

B.A. Northwestern University

Ph.D. Harvard University

Research

References

murtaugh@genetics.utah.edu

Charlie Murtaugh's PubMed Literature Search

Research

The pancreas is the site of two devastating diseases: type I diabetes, caused by autoimmune destruction of insulin-producing beta (β) cells, and pancreatic cancer, one of the deadliest human tumors.  The former involves the endocrine islets of Langerhans, which comprise several hormone-producing cell types; the latter is thought to arise from the exocrine compartment, which normally produces digestive enzymes.  By studying the development of these tissues, we hope to shed light on disease treatment and prevention.

Our lab focuses on how intercellular signaling pathways direct pancreas development, and how the roles of these pathways change as the pancreas itself changes during embryogenesis.  Using conditional gene activation and deletion in mice, we have shown that the Notch and Wnt/β-catenin pathways play critical and distinct roles at specific stages of pancreas development.  We have shown that Notch acts to block endocrine cell differentiation in the early embryonic pancreas, and slightly later also acts to block exocrine differentiation.  Notch thus traps multiple classes of progenitor cells in an immature state.  We do not yet know how these cells normally escape the influence of Notch, nor how Notch is able to influence so many developmental decisions, and further work in the lab will examine how upstream and downstream components of the pathway are regulated during, and themselves regulate, pancreas development.

The Wnt/β-catenin signaling pathway is thought to similarly inhibit differentiation in other organs, such as the intestine, thereby maintaining a stem cell compartment.  Wnts also act on intestinal precursor cells once they exit the stem cell zone, to promote endocrine development.  We investigated whether this pathway served similar roles in the pancreas, and found to our surprise that blocking Wnt/β-catenin signaling did not inhibit either progenitor cell maintenance or endocrine development.  Instead, the pathway is specifically required for early development of exocrine tissue, and rapidly downregulated after exocrine cells differentiate.  We want to determine exactly when and how this pathway acts during exocrine development, and whether regeneration of acinar cells in the adult, following injury to the pancreas, also requires Wnt/β-catenin.

Human pancreatic tumors and precancerous lesions exhibit upregulation of Notch pathway components, as do analogous lesions in mouse models of the disease.  By preventing the differentiation of precancerous cells, Notch may functionally synergize with other cancer-promoting signals.  We are now testing this potential synergy in a mouse model of pancreas cancer, using both gain- and loss-of-function approaches.  Our preliminary results suggest that Notch signaling indeed sensitizes pancreatic cells to transformation by the oncogene K-ras, and we are investigating the potential mechanism of this synergy, as well as determining precisely in what cell type it occurs, as this may represent the cell type from which pancreatic cancer originates.

 

(Left) Wildtype newborn mouse pancreas, exhibiting well-differentiated endocrine islet (is) and exocrine acinar (ac) tissue. (Right) Newborn mouse pancreas expressing activated Notch1 in epithelial cells. Islets and acini are replaced by progenitor cells incapable of differentiation.

 

References