We are interested in transcription factors that function in the regulation of cell fate determination during development. Our model system is the nematode C. elegans (a non-parasitic worm) that is widely used for developmental studies because of its small size, ease of culture in the laboratory, simple anatomy, rapid proliferation, and genetics. We are currently interested in several transcription factors (MyoD, E, Twist, and Mef-2) that have been identified in other systems as important for muscle formation. In collaboration with Dr. Andy Fire's group at the Carnegie Institution of Washington we have shown that the C. elegans MyoD and Twist factors are important for the formation and patterning of post-embryonic mesodermal cells including muscle. By studying the phenotypes that result from mutations in these genes we are beginning to define their exact roles in regulating the development of specific subsets of muscle cells in C. elegans. The mutants also provide a starting point for genetic screens to identify other factors operating in the regulatory hierarchy. A second aspect of our work focuses on the connection between cellular differentiation and the cell cycle. Usually, cells must exit the cell cycle (stop proliferating) in order to differentiate. This usually involves inhibition of the G1 cyclins (D and E) and their associated cyclin-dependent kinases (CDKs). Studies in other organisms and tissue culture have demonstrated a direct role for differentiation factors, such as MyoD in muscle cells, in antagonizing the action of G1 cell cycle factors. Using forward and reverse genetic approaches we have demonstrated that cyclin D and CDK-4/6 factors regulate the G1 phase of the cell cycle in C. elegans. Surprisingly, these G1 regulators only function during postembryonic development so they can not be important for muscle differentiation during embryogenesis. In contrast, cyclin E appears to be required for all cell division during development and is likely a common target of differentiation factors such as MyoD. We are currently exploring ways to address possible interactions between these cell cycle regulators and myogenic factors during post-embryonic development. We think the nematode offers the opportunity to study the balance of signals promoting either entry or withdrawal from the cell cycle in the context of normal development.
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