Research Focus "Developmental control of cell-cycle entry"
Mitogenic and anti-proliferative signals regulate cell division ultimately through their effects on the cell-cycle machinery. We follow genetic approaches to reveal signals that act upstream of the CDKs, with the goal of establishing how signal transduction pathways connect to the basic cell-cycle machinery.
As cells divide at specific times and different cell types likely respond to different signals, we focus on defects within a particular lineage or specific stage of development. We have developed efficient genetic screens for mutants in which cells either fail to divide or fail to withdraw from cell division. In one screen, five independent mutations have been identified that cause extra divisions in the Pn.p cell lineages during the second larval stage. Our preliminary analysis indicates that the temporal withdrawal of the Pn.p cells from the cell cycle involves cell-lineage dependent transcriptional activation of a CDK inhibitor of the CIP/KIP family. We will continue these approaches to reveal the regulatory pathways used to accomplish the correct timing of cell division during C. elegans development. These studies should provide a framework for developmental control of cell division in other systems.
A novel project focuses on a topic of great clinical and fundamental importance: the relationship between cell proliferation and differentiation. Terminally differentiated cells usually are no longer able to proliferate and retain very limited potential for regeneration and repair. Agents that induce differentiated cells to proliferate and/or de-differentiate to a stem-cell state are currently not available and could provide a breakthrough to regenerative medicine. Starting from a sophisticated genetic screen in C. elegans, we are trying to define the molecular mechanisms that limit proliferation of differentiated cells.