Our research focuses on the coordinated regulation of cell division and differentiation in the context of animal development. Our goal is to obtain a deeper understanding, at the molecular and systems level, of the mechanisms that control two important developmental decisions:
A human body consists of an estimated hundred trillion cells, of which a substantial fraction needs to be renewed every day. This makes cell division, and the balance between cell proliferation and differentiation, key aspects of normal development and health. Successful cell division requires coordination between chromosome segregation and cytoplasmic cleavage and leads to the formation of two daughter cells with the same genome. However, such daughter cells may differ in inherited constituents and signals they receive, and as a consequence take on different developmental fates.
Cell divisions that generate identical daughter cells and promote exponential increases in cell numbers are considered “proliferative” divisions. In contrast, asymmetric cell divisions often segregate the potential to proliferate and the commitment to differentiate to different daughter cells. This supports the maintenance of stable numbers of proliferating cells and promotes the generation of cell diversity. The difference in daughter cell fate may be achieved during the division process (intrinsically asymmetric division) or be acquired after division through external signals that are often derived from a niche. Adult stem- and precursor cells use one of these forms of asymmetric cell division to combine self-renewal with the production of differentiated daughter cells.
Clearly, the balance between proliferative and asymmetric cell divisions is crucial in the formation of the proper cell types and cell numbers during development and tissue homeostasis. Our goal is to obtain a deeper fundamental understanding of the molecular and systemic regulation of cell division in concert with differentiation. These studies start from a genetic model system, yet aim to contribute to a deeper understanding of human development and tissue regeneration, and to add improved insights in how disrupted proliferation/differentiation contributes to cancer and developmental abnormalities.
The nematode Caenorhabditis elegans offers a powerful model system to study cell division control during animal development. These animals have a transparent body and develop from the one-cell zygote to adult stage through a nearly invariant pattern of divisions. Thus, the division of all somatic cells can be followed within the developing animals and the exact times of cell division are known (Sulston et al; Dev. Biol. 1978, 1980). In combination with efficient genetics, this allows for a sensitive identification of cell cycle mutants and quantitative analysis of cell-division defects at a resolution that exceeds the possibilities in other animal models. Moreover, cells in the early embryo are large and the chromosomes and spindle asters cytologically observable, which are attractive aspects for cell biology and live imaging based approaches. Given the observed conservation of cell division processes and developmental pathways, C. elegans has the potential for major contributions towards understanding the coordination between cell division and differentiation in animal development.
Understanding the complex and dynamic regulation of cell proliferation and differentiation in development requires a multi-disciplinary approach. While much of our work is based on observations in vivo, we combine genetics and in vivo imaging in the nematode Caenorhabditis elegans with gene-expression profiling, mass spectrometry analysis, yeast two-hybrid studies, and experiments with cells in culture. In addition, we have recently started to include mathematical modeling and computer simulation in our studies of asymmetric cell division, in collaboration with the theoretical biology department at Utrecht University.