Although the pancreas is a relatively small organ, tucked away in a corner of the digestive tract, its diseases have a disproportionately large impact on humanity. Type I diabetes, also called juvenile onset diabetes, affects approximately one million Americans; the discovery of insulin has blunted the edge of what was for centuries a universally fatal disease, however, type I diabetes still remains a very serious and lifelong condition. Less common, but in many ways more terrifying, is pancreatic cancer, with which approximately 30,000 Americans are diagnosed each year. Nearly the same number will die, usually within a year of diagnosis. These diseases affect two distinct compartments of the pancreas: insulin-secreting endocrine cells are destroyed in type I diabetes, and pancreatic cancer is thought to arise from cells of the exocrine compartment, normally responsible for producing digestive enzymes. Early in development, however, both of these compartments arise from a common set of progenitors. My research, using mouse molecular genetics, aims to understand how progenitors are converted into mature endocrine and exocrine cells; this will yield insight into the treatment and prevention of these diseases. Mimicking the normal mechanisms by which insulin-producing beta (β) cells are made to differentiate, in the embryo, could allow their production in the clinic, for transplantation to cure type I diabetes. The malignancy of pancreatic cancer cells, on the other hand, depends on their escaping normal differentiation controls; understanding this escape mechanism will help identify targets for prevention and treatment.
The adult mammalian pancreas is comprised of two compartments, endocrine and exocrine, each containing a variety of cell types. Endocrine cells include insulin-producing β-cells, glucagon-producing alpha (α) cells, and several other, rarer, hormone-producing cells. These cells associate in the islets of Langerhans, and make up 5-10% of the mass of the pancreas. The rest is comprised of exocrine tissue, primarily enzyme-producing acinar cells, with a smaller population (5% or less of the total organ) of duct cells that channel the enzymes to the intestine. In terms of cell fate specification, an organ with such diverse composition represents a provocative challenge to the investigator; when one further considers the complex branching morphogenesis and growth that occurs concomitant with differentiation, the problem becomes more complex and more interesting.
Molecular studies of pancreas development have largely focused on transcription factors, yielding a growing list of such genes that are required for various aspects of differentiation and growth. Considerably less is known about the requirement in the developing pancreas for intercellular signaling pathways, such as Wnt, TGF-β, Notch, hedgehog and FGF. As such pathways can theoretically (and, increasingly, practically as well) be manipulated from the outside, and in many cases are implicated in disease pathologies, they represent potentially critical targets for therapeutic intervention.
My research to date has focused on the role played by two of these pathways, Notch and Wnt, in embryonic pancreas development. I developed a conditional transgenesis approach in the mouse, to determine the effects of Notch pathway activation at multiple stages and in an array of pancreatic sub-lineages. I found that the differentiation of both endocrine and exocrine progenitors, at a variety of stages, is blocked by Notch signaling, while differentiated cells are indifferent to the pathway. When their differentiation is inhibited by Notch signaling, cells do die but retain a slow-growing, progenitor-like state. Thus, Notch signaling appears to permit the persistence and self-renewal of progenitor cells, a potentially practically useful property. The Wnt signaling pathway plays a similar role in other tissues, and although several Wnt genes are expressed in the developing pancreas, nothing is known about their potential function there. The multifunctional protein β-catenin is absolutely required for the canonical Wnt signaling pathway; therefore we used a conditional gene knockout approach to remove its function. Surprisingly, the major defect in the β-catenin-deficient pancreas appears to be a loss of exocrine differentiation, suggesting that if Wnts play any role in the organ, it is in promoting, rather than inhibiting, exocrine differentiation.
Future work in my laboratory will further examine these and other pathways, especially their interaction and overlap. The two overarching questions in my research are: (1) how are β-cells specified, and (2) how do regulators of differentiation affect pancreatic tumorigenesis? In terms of the first question, having identified so far primarily negative regulators of endocrine cell fate, we are left with the open question of what promotes β-cell development. A first step is to interrogate the downstream mechanisms that Notch, and perhaps Wnt as well, use to divert cells away from a β-cell fate, as these must eventually intersect with positively-acting machinery. As to the second question, both Notch and β-catenin have been indirectly implicated in human pancreatic cancer, and we are directly examining their roles in a mouse model of the disease. These studies represent a transition from embryonic development to adult organ maintenance, where even less is known about transcription factors or signal ing activities. By developing novel tools to mark and manipulate of adult cells, we will gain novel insights into adult tissue dynamics and regulatory pathways, hopefully illuminating molecular mechanisms relevant to both diabetes and cancer.
References to Publications:
Kopinke, D. and L.C. Murtaugh. (2010) Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Developmental Biology 10:38.
Yun, S., Y. Saijoh, K.E. Hirokawa, D. Kopinke, L.C. Murtaugh, E.S. Monuki, E.M. Levine. (2009) Lhx2 links the intrinsic and extrinsic factors that control optic cup formation. Development 136:3895-906
De La O, J.-P., L.L. Emerson, J.L. Goodman, S.C. Froebe, B.E. Illum, A.B. Curtis, L.C. Murtaugh. (2008) Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl. Acad. Sci. USA 105:18907-12
Provot, S., H. Kempf, L.C. Murtaugh, U. Chung, D.-W. Kim, J. Chyung, H.M. Kronenberg and A.B. Lassar. (2006) Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development 133: 651-62
Murtaugh, L.C., A.C. Law, Y. Dor and D.A. Melton. (2005) Beta-catenin is required for pancreatic acinar but not islet development. Development 132: 4663-4674
Stanger, B.Z., R. Datar, L.C. Murtaugh and D.A. Melton. (2005) Direct regulation of intestinal fate by Notch. Proc. Natl. Acad. Sci. USA 102:12443-8
Murtaugh, L.C., B.Z. Stanger, K.M. Kwan and D.A. Melton. (2003) Notch signaling controls multiple steps of pancreatic differentiation. Proc. Natl. Acad. Sci. USA 100: 14920-14925
Lammert, E., G. Gu, M. McLaughlin, D. Brown, R. Brekken, L.C. Murtaugh, H.P. Gerber, N. Ferrara and D.A. Melton. (2003) Role of VEGF-A in vascularization of pancreatic islets. Curr. Biol. 13: 1070-1074
Zeng, L., H. Kempf, L.C. Murtaugh, M.E. Sato and A.B. Lassar. (2002) Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis. Genes Dev. 16:1990-2005
Murtaugh, L.C., L. Zeng, J.H. Chyung and A.B. Lassar. (2001) The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis. Dev. Cell 1: 411-422
Schweitzer, R., J.H Chyung, L.C. Murtaugh, A.E. Brent, V. Rosen, E.N. Olson, A. Lassar, C.J. Tabin. (2001) Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128: 3855-66.
Nielson, C., L.C. Murtaugh, J.H. Chyung, A. Lassar and D.J. Roberts. (2001) Gizzard formation and the role of Bapx1. Dev. Biol. 231: 164-174
Murtaugh, L.C., J.H. Chyung and A.B. Lassar. (1999) Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling. Genes Dev. 13: 225-37.
Nelson, C.E., B.A. Morgan, A.C. Burker, E. Laufer, E. DiMambro, L.C. Murtaugh, E. Gonzales, L. Tessarollo, L.F. Parada and C. Tabin. (1996) Analysis of Hox gene expression in the chick limb bud. Development 122: 1449-66
Huang, H.-C., L.C. Murtaugh, P.D. Vize and M. Whitman. (1995) Identification of a potential regulator of early transcriptional responses to mesoderm inducers in the frog embryo. EMBO J. 14: 5965-5973
LeBlanc-Straceski, J.M., K.T. Montgomery, H. Kissel, L. Murtaugh, P. Tsai, D.C. Ward, K.S. Krauter and R. Kucherlapati. (1994) Twenty-one polymorphic markers from human chromosome 12 for integration of genetic and physical maps. Genomics 19: 341-349
De La O, J.-P., L.C. Murtaugh (2009) Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling. Cell Cycle 8:1860-1864
De La O, J.-P., L.C. Murtaugh (2009) Notch signaling: where pancreatic cancer and differentiation meet? Gastroenterology 136:1499-1502
Murtaugh, L.C. and D. Kopinke (2008) Pancreatic stem cells. StemBook, doi/10.3824/stembook.1.3.1, http://www.stembook.org
Murtaugh, L.C. (2008) The what, where, when and how of Wnt/beta-catenin signaling in pancreas development. Organogenesis 4: 81-86
Murtaugh, L.C. and S.D. Leach. (2007) A case of mistaken identity? Nonductal origins of pancreatic “ductal” cancers. Cancer Cell 11: 211-213
Murtaugh, L.C. (2007) Pancreas and beta-cell development: from the actual to the possible. Development 134: 427-438
Murtaugh, L.C. and D.A. Melton. (2003) Genes, signals, and lineages in pancreas development. Ann. Rev. Cell Dev. Biol. 19:71–89
Murtaugh L.C., J. Cassiano J. and J.-P. De La O (2008). Chapter 8: Development of the endocrine and exocrine pancreas. In Lowy, A.M., S.D. Leach and P.A. Philip (eds.), Pancreatic Cancer (MD Anderson Solid Tumor Oncology Series). Springer, New York, NY.
Barrott, J.J., G.M. Cash and L.C. Murtaugh. Deletion of mouse Porcn blocks Wnt signaling and recapitulates the signature phenotypes of human focal dermal hypoplasia/Goltz syndrome. Under revision for PNAS.
Kopinke, D., M. Brailsford, R. Leavitt and L.C. Murtaugh. Lineage tracing reveals the dynamic contribution of Hes1+ cells to endodermal organs of the mouse. Revision submitted to Development.
Charles Murtaugh, Ph.D.
University of Utah
Department of Human Genetics
15 N. 2030 E. Rm. 4420B
Salt Lake City, UT 84112