A common interest of the people in the group is how cells make decisions about their fates during development. In particular we are interested in the actual nature of the decision event i.e. what do we mean by â€˜a decisionâ€™ in the context of cells and development, and what are the molecular processes associated with this event.
For many years we studied this process in Drosophila where genetic analysis allowed the identification of genes associated with this process. Exhaustive studies in many system by us and others revealed that development is associated with a sequence of changes in state that take a cell from a naÃ¯ve state to a differentiated situation. The states are associated with cell type specific gene regulatory networks (GRN), usually driven by transcription factors, and a few signalling pathways which seem to be involved in many processes irrespective of specific GRNs.
Understanding the process of cell fate decisions could thus be formulated as a problem of unwrapping the impact that sequential interactions between Signalling Pathways and Transcriptional networks have on the phenotypes of cell populations. Analysis and consideration of these processes in Drosophila led us to the propose that all cell fate decision processes are characterized by an intermediate, the transition state, which is a consequence of the dynamics of the process. A change of cell state or fate (from A to B) can be divided into two steps: from the original state (A) to the transition state (A/B) and from this to the new state (B) (Fig. 1). A transition state is characterized by coexpression of genes from both states (hence the A/B identity) and is probabilistic i.e from here a cell can either move to a new state or return to the state of origin, and At the level of a population of cells, this probabilistic nature of the transition state is the source of a regulative mechanism: not all cells that can go from A to B will adopt the B state and the transition state provides a source of variation for selection.
The reasoning behind this concept lies in the observation of cell fate decisions in different systems in Drosophila where it is possible to observe, often, intermediate states characterized by heterogeneous expression of the genes associated with the decision at the level of the population (Fig. 2). The heterogeneity resolves itself and only some cells from the pool in the transition states adopt the new fates with the rest either returning to the state of departure or getting lost. We believe that the transition state provides a universal paradigm for cell fate decisions and are interested in understanding its molecular underpinning. At the moment, we do this following three related lines of research with a focus on mouse embryonic stem cells and Drosophila intestinal stem cells. The reason for the interest in stem cells is indicated in the box 1.
Â Our work uses a combination of modern genetics and cell biology with live imaging, quantification and modelling. NB for us modelling is not an end in itself but another tool. A tool which is increasingly necessary to think about developmental events which depend on multiple variables and have an essential dynamic component.