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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

My lab studies the role of cell-to-cell signaling in mammalian development and disease.  Much of our work focuses on the pancreas, which in the adult comprises multiple cell types but which develops in the embryo from clusters of multipotent progenitor cells.  We want to understand how those cells are instructed to differentiate into the mature constituents of the organ: endocrine islets, digestive-enzyme producing acinar cells, and duct cells.  Loss or dysfunction of mature pancreatic cells causes several diseases, including diabetes, pancreatitis and cancer, and we are interested in the intercellular signaling processes that prevent or precipitate these conditions.  Our studies make use of genetically-modified mice, and the following include some of our major projects:

Wnt signaling in pancreatic development and regeneration.  The Wnt signaling pathway appears to play multiple roles in the developing and adult pancreas.  In early phase, Wnt signaling inhibits pancreas development altogether (favoring instead the formation of other gut organs such as stomach and lung), while in later embryogenesis the pathway is essential for expansion of multipotent progenitor cells that give rise to acini, ducts and islets.  After birth, Wnt signaling is required for normal growth of acinar cells, as well as for replenishment of acinar cells in a mouse model of pancreatitis.

“Identity theft” in pancreatic cancer.  The stability of cell fates in the adult pancreas appears to be lost during tumor formation, as we have shown that ductal pancreatic cancer arises from acinar cells that lose their normal cellular identity.  Furthermore, we find that this process is driven by the Notch signaling pathway, which also inhibits acinar differentiation in the embryo.  Our recent studies indicate a general role for pro-acinar regulators in preventing pancreatic cancer initiation, suggesting that abnormal differentiation could contribute to disease risk in humans.

Modeling a human birth defect syndrome.  Focal dermal hypoplasia (FDH) is an X-linked dominant disorder causing highly variable and pleiotropic phenotypes that range from skin lesions to dramatic malformations of the limbs and body wall.  FDH is caused by mutations in the human PORCN gene, which encodes a component of the Wnt signaling pathway.  We have generated a mouse model of this syndrome, based on deletion of the mouse gene, and are using tissue-specific knockouts to understand the etiology of FDH and explore whether disorders of skin and body wall development -- relatively common human birth defects -- reflect abnormalities of Wnt signaling.  We are also using this genetic tool to probe the role of Wnt signaling in the developing and pancreas.

Notch and oncogenic Ras synergistically induce precancerous lesions from adult acinar cells (D), while each pathway alone has little or no tumor-inducing activity (B-C). (From ref. 2.)

 

References