Programming blood stem cells during embryonic development
WIMM OxfordGeneral/Lab Fax: +44 (01865) 222737
Cells are programmed during embryonic development. As they move through the embryo, they receive signals from neighbouring cells thereby establishing their gene expression programmes. The agents of this programming are transcription factors whose expression is initially controlled by the embryonic signals and therefore by other transcription factors. Transcriptional regulatory networks are established, which become independent of the initiating signals but may remain dependent on maintenance signalling. Thus, as cells differentiate and arrive in their niches, their networks become stabilised. Understanding how these networks are established and maintained is the main interest of our lab. Our focus is on blood and the cardiovascular system. We have a particular interest in the programming of blood stem cells, an understanding of which will inform our understanding of many diseases including leukaemias. For example, genetic and environmental insults can be modelled and both the consequences and actions that might induce recovery can be predicted. In addition, realising the potential of stem cells to repair damaged or lost tissue will depend on the ability to manipulate these cells which in turn will benefit from a better understanding of these molecular circuitries. We are studying these processes in amphibia and fish (Xenopus and zebrafish), whose embryos are laid in large numbers and develop externally. Techniques have been developed to manipulate signalling regimes and transcription factor activities in these embryos as they develop. Methodologies include genetic mutations, antisense depletion, mRNA injection, transgenesis, dominant negative expression and small molecule inhibition. The consequences of perturbation for the expression of large numbers of genes can readily be determined using automated in situ hybridisation. Cell lineages have been traced enabling targeted perturbations. In addition, we have the capacity to study development in embryo explants to simplify development in defined conditions. In these ways, we are defining how embryos programme blood and the cardiovascular system, and we are recapitulating these processes in vitro.