Genetics of thymopoiesis and T cell development in vertebrates
A forward genetic screen in zebrafish was undertaken in order to establish the genetic basis of thymopoiesis and T cell development in vertebrates and about 40 mutant lines have been established. The mutant genes so far identified by positional cloning show that the zebrafish model is an excellent tool to define novel genetic pathways important for T cell development. For instance, we have identified an evolutionarily conserved function of the ikaros transcription factor in zebrafish lymphopoiesis and defined the key requirement of the c-myb transcription factor for definitive haematopoiesis.
The molecular nature of other genes identified in this screen also support the notion that the overall mechanism of thymopoiesis is well conserved in vertebrates, and we are working towards the application of these findings to explain previously uncharacterized immunodeficiency syndromes in humans.
Using genetic interaction analysis, we aim at generating a draft version of the genetic networks underlying vertebrate T cell development. We also use long-term live imaging analysis with our mutants and novel transgenic fish lines to further examine the genetic basis of essential steps during thymopoiesis, i.e. migration and specification, and to establish their spatial and temporal characteristics. Here, we are exploiting the unique possibility in fish of interfering in vivo with single and multiple gene functions through sequence-specific genetic interference.