Research Interests

Developmental genetics of germline proliferation in C. elegans

My lab studies the developmental genetics of cell proliferation control using C. elegans as a model system.  

During the development and maintenance of tissues and organs, cells must decide whether, when, where and how much to proliferate. Improper control of cell proliferation can lead to developmental defects and cancer. We are focusing on the relatively unexplored area of the control of pattern and extent of germline proliferation as a model for this process. In particular, we are interested in signaling between the somatic gonad and the germ line that influences germline proliferation during their co-development. Our entry into this area is via analysis of C. elegans mutations that cause germline tumors.

To understand proliferation control, we have characterized several mutants that cause proximal germline tumor formation. In addition, we have uncovered the key anatomical and molecular events that underlie tumor formation in these mutants. These tumors result from a delay in the initial onset of differentiation during germline development. This delay causes an appropriate cell-cell contact between particular gonad cells and undifferentiated (mitotically competent) germ cells. We are using our detailed knowledge of proximal germline tumor formation to design and carry out large-scale genetic screens – both classical and RNAi-based screens – designed to identify genes that enhance tumor formation. These approaches have identified candidate genes including genes involved in the insulin signaling pathway.

C. elegans germ cells are also a model for studying stem cells. The germ line contains a self-renewing or putative stem cell population. A large body of work implicates a Notch receptor signaling pathway to maintain germline mitotic fate, including a niche-like distal tip cell (DTC) that produces ligands of the DSL family. The anatomy of this system is relatively simple and accessible, and the genetic power of C. elegans offers great potential for furthering our understanding of niche-stem cell interactions in general. However, the spatial and temporal dynamics of germ cell division within the mitotic zone are not well defined. We are actively pursuing methods to better characterize these dynamics including ways to label putative germline stem cells, so as to follow their division patterns in live animals. We have pioneered a wet/dry statistical approach to investigate the dynamics of cell division in the proliferation zone. Our studies led to the unexpected result that cell division frequency is lower in cells that directly contact the distal tip cell, consistent with a model for a niche/stem cell/transit-amplifying cell system similar to mammalian stem cell systems such as the gut crypts.

Finally, in collaboration with several computer science groups we are perusing computational modeling methods that can be applied to developmental biology.