Charles Murtaugh's Lab Page
Charles Murtaugh's PubMed Literature Search
My lab studies the role of cell-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:
The Wnt and Notch pathways are potent regulators of cell fate determination, and we have implicated them in specific aspects of pancreas developmental biology. An emerging theme in our recent studies is that these pathways remain active in the adult organ, and exert similar effects at multiple developmental stages. Thus, Wnt signaling promotes the self-renewal of acinar-like progenitor cells as well as mature acinar cells, e.g. during regeneration from injury, while Notch signaling both promotes duct development in the embryo and maintains ductal differentiation in the adult. We are currently examining the possibility that these pathways cross-regulate each other, and further exploring the mechanisms by which they regulate pancreatic cell fate.
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 normally promotes ductal differentiation at the expense of acinar. 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.
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 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. 9.)