Charles Murtaugh

Associate Professor of Human Genetics

Charlie Murtaugh

B.A. Northwestern University

Ph.D. Harvard University

Research

References

murtaugh@genetics.utah.edu

Charles Murtaugh's Lab Page

Charles Murtaugh's PubMed Literature Search

Research

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:

Wnt and Notch signaling in pancreatic development and regeneration

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.

“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 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.

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 pancreas.

Charlie Murtaugh's Figure

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.)

References

  1. Keefe MD, Wang H, De La O J-P , Khan A, Firpo MA, Murtaugh LC (2012) β-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells. Disease Models and Mechanisms, 5:503-14
  2. Kopinke D, Brailsford M, Pan FC, Magnuson MA, Wright CVE, Murtaugh LC (2012) Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas. Developmental Biology, 362:57-64
  3. Barrott JJ, Cash GM, Smith AP, Barrow JR, Murtaugh LC (2011) Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome. Proc Natl Acad Sci USA, 108:12752-7
  4. Kopinke D, Brailsford M, Shea J, Leavitt R, Scaife C, Murtaugh LC (2011) Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas. Development, 138:431-41
  5. Kopinke D, Murtaugh LC (2010) Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Developmental Biology, 10:38.  (“Highly accessed” publication, per journal website.)
  6. De La O J-P, Murtaugh LC (2009) Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling. Cell Cycle, 8:1860-1864
  7. Murtaugh LC, Kopinke D (2008) Pancreatic stem cells. StemBook, doi/10.3824/stembook.1.3.1, http://www.stembook.org
  8. Murtaugh LC (2008) The what, where, when and how of Wnt/beta-catenin signaling in pancreas development. Organogenesis, 4:81-86
  9. De La O J-P, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB, Murtaugh LC (2008) Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA, 105:18907-12
  10. Murtaugh LC (2007) Pancreas and beta-cell development: from the actual to the possible. Development, 134: 427-438

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Last Updated: 6/25/14