Studies on Gata1: Cell Cycle, Survival and Differentiation
De rol van Gata1 in de cel cyclus, overleving en differentiatie
Gata1 is a zinc finger transcription factor essential for erythropoiesis. It is also expressed in other haematopoietic lineages and in Sertoli cells of the testis. Gata1 has been linked to the regulation of the cell cycle, differentiation and survival of the cells in which it is expressed. In the erythroid system, absence of Gata1 leads to apoptosis at the proerythroblast stage. Gata1 levels are downregulated at the last stages of normal erythroid differentiation. Gata1 overexpression causes a proliferative phenotype in cells beyond the proerythroblast stage that renders them unable to arrest the cell cycle, a requirement for terminal differentiation. However the phenotype of Gata1 overexpressing cells is rescued in the presence of wildtype cells, as occurs in heterozygous Gata1 overexpressing females. This phenomenon was described to be regulated by a signalling mechanism named Red Cell Differentiation Signal (REDS). One of the aims of my thesis project was to determine the nature of REDS, as it could be a signalling mechanism involving cells of either the same or of a different type, i.e. it could be a homotypic or a heterotypic mechanism. By means of a “conditional” Gata1 allele, which is inactivated upon the action of Cre recombinase, I ablated the erythroid wildtype population in the Gata1-overexpressing heterozygous females. The compound females died of anaemia during gestation, showing that the ablated population of cells is the source of REDS, i.e. REDS is a homotypic signalling mechanism.