Cell Biology, Neurobiology & Anatomy

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Stephen A. Duncan, D Phil
Marcus Professor of Human and
Molecular Genetics
Director, Program in Regenerative Medicine

Department of Cell Biology, Neurobiology & Anatomy
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226-0509

Phone: (414) 456-8602
FAX: (414) 456-6517
Email: duncans@mcw.edu

 Stephen A. Duncan, D Phil

Education:
D Phil, Oxford University, 1992
Postdoctoral, Rockefeller University, New York

Graduate Programs:
Program in Cell and Developmental Biology

Positions Available:
Positions are currently available for PhD students and Postdoctoral Fellows. Please contact Dr. Stephen Duncan at duncans@mcw.edu or visit our Postdoctoral Positions web page.

Research Area: Molecular mechanisms underlying mammalian development

Visit the Program in Regenerative Medicine website

Development of a simple two-cell embryo to a complex multicellular organism is a highly dynamic procedure requiring orchestrated cell movements and multiple interactions between cells and their surroundings. As cells differentiate, not only do they receive extra-cellular signals but they secrete and display signals of their own, thereby defining the makeup of their local environments. The result of these intercellular communications is the controlled differentiation of populations of progenitor cells to produce novel cell types. The phenotype of any individual differentiated cell is determined by the gamut of genes that cell expresses and this process is largely regulated at the level of transcription. In order to comprehend the molecular mechanisms controlling embryonic development my laboratory is, therefore, attempting to understand how transcription factors interact with extra-cellular signaling mechanisms to drive cellular differentiation.

Most organs are a complex array of different cell types and tissues, all of which dynamically interact to regulate organogenesis, making it difficult to measure the contribution of a specific transcription factor to overall organ or tissue development. However, the liver, in which 90% of the cells are hepatocytes, offers an attractive and relatively simpler system in which to study the role of transcription factors during morphogenesis and development. We have taken a molecular genetics approach using transgenic mice (knockouts/knockins) and genetically modified embryonic stem (ES) cells to determine which transcription factors and cell signaling molecules are required to drive hepatic development. In addition to using traditional transgenic approaches we are one of a few labs using tetraploid-mediated transgenics to produce mouse embryos directly from genetically altered ES cells. This extremely powerful genetic tool allows the production of mouse embryos with phenotypes which are normally lethal and so enables an analysis of events crucial during early stages of mammalian embryogenesis. Using this approach we have found that the transcription factors HNF-4 and HNF-3 are important regulators of hepatocyte differentiation and are in the process of evaluating the interaction of HNF-4 and HNF-3 gene expression with existing signal transduction pathways.

In addition to examining cellular differentiation in the context of mouse embryos we have begun to research similar processes using mouse, primate and human embryonic stem cells.  Embryonic stem cells renew indefinitely, can be genetically manipulated, and are pluripotent, meaning they have the capacity to differentiate into all cell types in the body.  We believe that embryonic stem cells can be used to examine the basic molecular events that control human development as well as to identify pathways that go awry in a variety of diseases.  We are currently using federally approved human embryonic stem cell lines to examine the role of specific factors that have been linked to diabetes, heart disease, and control of cholesterol levels.  By controlling the expression of such factors during the formation of pancreatic, heart and cardiac cells from embryonic stem cells we believe that we will generate cell models that can be used to understand the fundamental mechanisms underlying human pathologies and development.

Research in the lab is currently funded by the Marcus family, Sophia Wolf Quadracci Memorial Fund for Stem Cell Research, as well as grants from Advancing a Healthier Wisconsin and the National Institutes of Health

 

 

 

 

Duncan lab

The Duncan Lab:
Front Row (left to right): Stephen Duncan, Gena Konopka, Michele Battle
and Mariam Hartley
Second Row: Jennifer Luebke-Wheeler, Wendy Garrison, Chhinder Sodhi, Rong Zhao,
Fereshta Parviz (former postdoctoral fellow) and Jixuan Li
Back Row: Allistar Watt (former postdoctoral fellow), Dong Zhao, Alexandra Lerch-Gaggl,
Jamil Haque (former graduate student) and Kai Sun

 

 

Selected Publications:
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Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ, Duncan SA.  Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol. 2008 Mar 20
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Junctional adhesion molecule-A is critical for the formation of pseudocanaliculi and modulates E-cadherin expression in hepatic cells.  J Biol Chem. 2007 Jul 9
  •  

Watt AJ, Zhao R, Li J, Duncan SA: Development of the mammalian liver and ventral pancreas is dependent on GATA4.  BMC Dev Biol.  23;7(1):37, 2007
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Lerch-Gaggl AF, Sun K, Duncan SA: Light chain 1 of microtubule-associated protein 1B an negatively regulate the action of Pes1.
J Biol Chem. 282(15):11308-16, 2007. Epub 2007
  •  

Battle, MA, G Konopka, F Parviz, AL Gaggl, C Yang, FM Sladek and SA Duncan: Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver.
Proc Natl Acad Sci USA. 103:8419-24, 2006.
  •  

Garrison WD, MA Battle, C Yang, KH Kaestner, FM Sladek and SA Duncan: Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology 130:1207-20, 2006.
  •  

Sodhi CP, J Li and SA Duncan: Generation of mice harbouring a conditional loss-of-funcion allele of Gata6. BMC Dev Biol 6:19, 2006.
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Zhao R, AJ Watt, J Li, J Luebke-Wheeler, EE Morrisey and SA Duncan: GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol 25:2622-31, 2005.
  •  

Watt AJ, MA Battle, J Li and SA Duncan: GATA4 is essential for formation of the proepicardium and regulates cardiogenesis.
Proc Natl Acad Sci USA 101:12573-12578, 2004.
  •  

Lazarevich NL, OA Cheremnova, EV Varga, DA Ovchinnikov, EI Kudrjavtseva, OV Morozova, DL Fleishman, NV Engelhardt and SA Duncan: Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology 39:1038-47, 2004.
  •  

Parviz F, C Matullo, WD Garrison, L Savatski, JWAdamson, G Ning, KH Kaestner, JM Rossi, KS Zaret and SA Duncan: Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34:292-6, 2003.
  •  

Watt AJ, WD Garrison and SA Duncan: HNF4: A central regulator of hepatocyte differentiation and function. Hepatology 37:1249-53, 2003.
  •  

Tirona RG, W Lee, BF Leake, LB Lan, CB Cline, V Lamba, F Parviz, SA Duncan, Y Inoue, FJ Gonzalez, EG Schuetz and RB Kim: The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9:220-4, 2003.
  •  

Duncan SA: Mechanisms controlling early development of the liver. Mech Dev 120:19-33, 2003.
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Parviz F, J Li, KH Kaestner and SA Duncan:.Generation of a conditionally null allele of hnf4alpha. Genesis 32:130-3, 2002.
  •  

Lerch-Gaggl A, J Haque, J Li, G Ning, P Traktman and SA Duncan: Pescadillo is essential for nucleolar assembly, ribosome biogenesis and mammalian cell proliferation. J Biol Chem. 2002 (Sep 16). [Full Text]
  •  

Misra RP, SK Bronson, Q Xiao, W Garrison, J Li, R Zhao and SA Duncan: Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation. BMC Biotechnol 2001,1(1):12. [Full Text]
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Duncan SA: The pancreas and its heartless beginnings. Nat Genet 27:355-6, 2001.
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Duncan SA and A Watt: BMPs on the road to hepatogenesis. Genes Dev 15:1879-1884, 2001. [Full Text]
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Haque J, S Boger, J Li, and SA Duncan: The murine pes1 gene encodes a nuclear protein containing a BRCT domain. Genomics 70:201-10, 2000.
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Duncan SA: Transcriptional regulation of liver development. Dev Dyn 219:131-142, 2000. [Full Text - (in either pdf or html format]
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Li J, G Ning and SA Duncan: Mammalian hepatocyte differentiation requires the transcription factor HNF-4a. Genes Dev 14:464-474, 2000.
  •  

Shih D, MA Navas, S Kuwajima, SA Duncan and M Stoffel: Impaired glucose homeostasis and neonatal mortality in HNF-3a deficient mice. Proc Natl Acad Sci USA 96:10152-10157, 1999.
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Duncan SA, MA Navas, D Dufort, J Rossant and M. Stoffel: Regulation of a transcription factor network required for differentiation and metabolism. Science 281:692-695 1998.
  •  

Stoffel M and SA Duncan: The MODY1 transcription factor HNF-4a regulates expression of genes required for glucose transport and metabolism. Proc. Natl. Acad. Sci. USA. 94:13209-13214, 1997.
  •  

Duncan SA, A Nagy and W Chan: Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: Tetraploid rescue of HNF-4-/- embryos. Development 124:279-287, 1997.
  •  

Chen WS, K Manova, DC Weinstein, SA Duncan, AS Plump, VR Prezioso, RF Bachvarova and JE Darnell, Jr.: Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes and Dev. 8:2466-2477, 1994.
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Duncan SA, K Manova, W Chen, P Hoodless, DC Weinstein, RF Bachvarova and JE Darnell, Jr.: Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc. Natl. Acad. Sci. USA. 91:7598-7602, 1994.

 

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