David Wotton, PhD
Cell cycle reulation and dis-regulation of TGF-b
The Wotton laboratory uses cell and molecular biology techniques to understand how mammalian development and the cell cycle are regulated in response to signaling via the transforming growth factor beta and retinoic acid pathways. A major new area of research is the use of mouse mutant models to understand the importance of these pathways in vivo. Some of the generation of mouse mutants has been through the Transgenic Mouse Core. The specific focus of the laboratory is on the regulation of transforming growth factor beta and retinoic acid signaling by transcriptional corepressors, particularly a protein called TGIF which regulates both pathways. Mouse mutants of TGIF have numerous defects including defects in placental and bone development, and a collaboration with Dr. Theresa Guise is currently underway to understand the nature of the bone defects. Preliminary results suggest a role for TGIF in regulating osteoclast and osteoblast levels. Detailed analysis of the mutant mice has made expensive use of the Research Histology Core.
TGIF is amplified in a subset of human esophageal tumors, and the laboratory is currently trying to understand how TGIF regulates cell cycle progression. One simple model is that increased TGIF prevents the growth inhibitory actions of transforming growth factor beta signaling. However, from mouse models it is becoming clear that loss of TGIF can also have dramatic consequences on the cell cycle. Cells lacking TGIF appear to become polyploid and undergo cell cycle arrest, in a transforming growth factor beta independent manner. Analysis of these defects in both mice and the cells derived from them has made extensive use of the Research Histology Core and Cell Sorter Facility.