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 somatic cells and the germ line that influences germline proliferation during development. We use the model organism C. elegans for our studies.

We have identified and analyzed C. elegans mutants that contain restricted areas of uncontrolled proliferation (tumors) in the germ line (Pepper et al., 2003a Genetics; Pepper et al., 2003b Developmental Biology; Killian and Hubbard, 2004 Development; Voutev et al. 2006 Developmental Biology). Our studies revealed a several soma-germline interactions important for germline proliferation. These approaches also led to a new concept: the "latent niche" (McGovern et al., 2009 PNAS). Some germline tumors in C. elegans form as a result of inappropriate interaction with a latent niche, a cell type that does not normally act as a niche but that can (like a stem cell niche) promote the proliferation, survival or renewal of cells it contacts. We are using our detailed knowledge of germline tumor formation to carry out large-scale genetic/RNAi screens to identify genes that influence tumor formation and growth. We have identified several candidate genes and pathways, including genes involved in the insulin signaling pathway (Michaelson et al., submitted).

Enhancement of tumor formation after Sh1 ablation in glp-1(ar202)

C. elegans germ cells are a self-renewing stem cell population. A large body of work implicates a Notch receptor signaling pathway to maintain germline mitotic fate, including a single niche-like distal tip cell (DTC) that produces the DSL family ligand LAG-2. 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 started with a wet/dry statistical approach to investigate the dynamics of cell division in the proliferation zone (Maciejowski et al., 2006 Developmental Biology). 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. We are actively pursuing methods to better capture these dynamics in live animals.

Germ cell and distal tip cell membranes labelled in live worm

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