Research
Our lab uses C. elegans genetics, biochemistry, and cell biology techniques to reveal the mechanisms that direct cells to either divide or arrest during development. We are interested in this decision since cells that are unable to properly control cell divisions can result in developmental defects and cancer. To understand how the cell-cycle machinery is controlled in response to developmental signals we use the highly regulated cell divisions of C. elegans as a model system.
We can examine in great detail the interaction between developmental signals and the cell-cycle machinery by taking advantage of several characteristics of C. elegans. For example, development proceeds through a highly reproducible cell lineage which allows studies with single-cell resolution. We focus on six precursor cells (called VPCs) that give rise to the adult vulva. The VPCs display a developmental cell-cycle quiescence that requires the members of the conserved p27 and pRb tumor suppressor families. Interestingly, our previous studies revealed a role of the Cdc14 phosphatase as a regulator of p27, a function which has subsequently been shown to be conserved with Humans. Our current studies to further uncover the developmental mechanisms used to control cell divisions are briefly described below.
Ongoing projects in the lab include:
1. Define the mechanisms used to regulate cdc-14 activity during development. We have observed that cdc-14 is ubiquitously expressed throughout C. elegans development. However, the phenotype of the cdc-14 null mutation indicates that cdc-14 functions within specific cells to impose periods of temporary cell-cycle quiescence. We are using a combination of genetic and biochemical techniques to uncover components of the pathway controlling cdc-14 activity and to understand how these components interact to control cell divisions.
2. Determine the functions of newly identified regulators of cell-cycle entry and exit. We performed a genome-wide RNAi screen to identify genes that control cell divisions. The screen took advantage of a mutation within a Notch-family receptor to direct the inappropriate differentiation of the VPCs into easily observed protrusions, called pseudovulvae. Using this genetic background we screened a genome-wide RNAi library of approximately 15,500 individual clones to identify genes required for normal VPC cell cycle arrest. Over 50 genes were identified that have roles in the production of VPCs. Projects are aimed at understanding how these genes are organized into a genetic network that regulates cell-cycle entry and exit.