Coordination of chromosome segregation with cytokinesis
During mitosis, the physical division of one cell into two is called cytokinesis. Cytokinesis must be tightly coordinated with mitotic chromosome segregation to ensure that each daughter cell receives adequate cytoplasm and a single copy of the genome. This coordination is ensured by a set of proteins required for cytokinesis that localize on the chromosomes during metaphase and transition to the division plane during chromosome segregation, on a structure called the "central spindle". Using the power of genetics and live–cell analysis, we are studying how these central spindle-bound proteins promote efficient division between the separated chromosomes.
Regulation of contractile ring assembly and constriction
Cytokinesis is accomplished via constriction of an equatorially localized contractile ring composed of filamentous actin and the motor protein myosin II. Assembly and constriction of the contractile ring are dependent on the small GTPase Rho, which promotes actin polymerization and myosin II motor activation. In parallel, Rac GTPases act to inhibit contractility during cytokinesis and thus must be inactivated for cytokinesis to occur. A focus of our lab is to understand the interplay between stimulatory and inhibitory signaling that promotes efficient constriction of the contractile ring to accomplish cell division.
Genetics of cell division
Forward genetics is a powerful tool for both gene discovery and for identifying complex molecular interactions. In our lab, we isolate cell division-defective mutations that affect gene function in a conditional (temperature-sensitive) manner. At restrictive temperature embryonic cell division fails, but at permissive temperature the embryos develop into adulthood. The "tunable" nature of these mutants provides a sensitized background to screen for genetic disruptions that either enhance or suppress the cell division defects. We are also cloning uncharacterized mutants with exciting cell division defects using both traditional and cutting-edge genetic mapping techniques.
The Mighty Worm
The tiny soil dwelling nematode Caenorhabditis elegans is a powerful genetic model system to study cell division. The embryos are optically clear and embryonic cell divisions are temporally invariant, and are thus highly amenable to quantitative live-imaging analysis upon gene disruption. Importantly, the core cell division machinery active in C. elegans is evolutionarily conserved with that in human cells. Thus, our research in C. elegans will likely lead to the identification of novel drug targets to treat human disease.