Marcus Professor of Human and Molecular Genetics
Vice-Chairman, Cell Biology, Neurobiology & Anatomy
Director, MCW Program in Regenerative Medicine and Stem Cell Biology
Medical College of Wisconsin
Department of Cell Biology, Neurobiology & Anatomy
8701 Watertown Plank Road
Milwaukee, WI, 53226-0509
(414) 955-6517 (fax)
D Phil, Oxford University, 1992
Postdoctoral, Rockefeller University, New York
Program in Cell and Developmental Biology
Regenerative Medicine Web Site
Positions are currently available for PhD students and Postdoctoral Fellows. Please contact Dr. Stephen Duncan at email@example.com or visit our Postdoctoral Positions web page.
Molecular mechanisms underlying mammalian development
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.