One of the goals of modern developmental biology is to comprehend the molecular and genetic mechanisms that guide the formation of organs during embryogenesis. Our principal interest is to understand the integration of transcriptional and intercellular signaling mechanisms that control organogenesis in mammals.
We have chosen to study the embryonic development of the pancreas. Pancreogenesis requires the coordinated formation of two unique tissues arising from shared precursor cells:endocrine tissue organized into islets of Langerhans that secrete polypeptide hormones and exocrine tissue comprising acini and ducts that secrete digestive enzymes and channel those secretions to the intestine. Defects in the proper formation or maintenance of islet cells are principal causes of diabetes, defects in exocrine cells cause pancreatitis and the major forms of pancreatic cancer. We would like to understand the mechanisms for the formation and maintenance of the pancreas that are relevant to the causes or the potential treatment of these diseases.
The following research projects are designed to understand the transcriptional regulatory genes that initiate pancreogenesis at a specific point along the embryonic gut, control the development of the gland including morphogenesis and cellular differentiation, and maintain the pancreas-specific functions of the mature gland. Ongoing projects investigate - The regulatory mechanisms that resolve the islet and acinar cell lineages during embryonic development. - The nature of the morphogenetic process that transforms the simple pancreatic epithelium into a dynamic one with the genesis of islets toward the center and acini around the periphery. - The program of transcriptional control for the initiation and maintenance of the acinar cell developmental program. - The temporally distinct transcription factor networks established by PTF1a, a key regulator of multiple stages of pancreatic development. - The integration of intercellular developmental signals and lineage- or field-specific transcriptional regulators at transcriptional enhancers of genes that control pancreatic organogenesis. This involves developing new lines of mice with transgenic sentinels that report the activation of specific signaling pathways in vivo and in vitro. The information from these projects will be useful for devising in vitro schemes to manipulate the development of human embryonic stem cells toward functional insulin-producing cells for potential transplantation therapy of diabetics.
RESEARCH INTERESTS
Organogenesis
Transcriptional control of development
Evolution of developmental programs
RECENT PUBLICATIONS
Kong, Y.M., MacDonald, R.J., Wen, X-F., Yang, P., Barbera, V. and Swift, G.H., "A genome-wide survey of transcription factor expression in fetal and adult human organs" Gene Expression Patterns, 6:678-686, 2006
Beres, T.M., Masui, T., Swift, G.H., Shi, L., Henke, R.M., and MacDonald, R.J., "PTF1 is an organ-specific and Notch-independent bHLH complex containing the mammalian Suppressor of Hairless (RBP-J) or its paralogue RBP-L" Molecular and Cellular Biology, 26:117-130, 2006
Hale, M., Kagami, H., Shi, L., Holland, A.M., Elsasser, H.P., Hammer, R.E., and MacDonald, R.J., "The homeoprotein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas" Developmental Biology, 286:225-237, 2005
Masui, T., Long, Q., Beres, T.M., Magnuson, M.A., and MacDonald, R.J., "Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex" Genes & Development, 21:2629-2643, 2007
Masui, T., Hale, M.A., Swift, G.H., and MacDonald, R.J., "Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood" Molecular and Cellular Biology, PMID: 18606784:Epub ahead of print, July 2008
SIGNIFICANT PUBLICATIONS
Holland, A.M., Hale, M.A., Kagami, H., Hammer, R.E., and MacDonald, R.J., "Experimental control of pancreatic development and maintenance" Proc. Nat’l. Acad. Sci. USA, 99:12236-12241, 2002
Swift, G.H., Hammer, R.E., MacDonald, R.J., and Brinster, R.L., "Tissue-specific expression of the rat elastase I gene in transgenic mice." Cell, 38:639-646, 1984
Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J., and Rutter, W.J., "Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease." Biochemistry, 24:5294-5299, 1979
Goodman, H.M., and MacDonald, R.J., "Cloning of hormone genes from a mixture of cDNA molecules." Methods in Enzymology, 68:75-90, 1979
Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R.J., Wright, C.V.E., "The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors" Nature Genetics, 32:128-134, 2002
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