Control of mRNA Translation in Erythropoiesis

The balance between proliferation and differentiation of committed hematopoietic progenitors is under tight control to maintain the progenitor pool and ensure maturation in response to physiological demand. Whereas development of the different hematopoietic lineages requires the coordinate expression of transcription factors, the balance between proliferation and differentiation is controlled by growth factors. These include cytokines such as erythropoietin (Epo) and granulocyte-colony stimulating factor (G-CSF) required for differentiation into specific lineages, as well as growth factors that enhance proliferation and delay differentiation of progenitors such as stem cell factor (SCF) and the ligand for FMS-like tyrosine kinase 3 (Flt3- ligand). To investigate how the balance between expansion and differentiation of erythroid progenitors is controlled by growth factors, we used a model in which erythroid progenitors proliferate in the presence of Epo, SCF and glucocorticoids while they maintain the capacity to differentiate upon addition of Epo alone. SCF- driven proliferation and inhibition of differentiation is dependent on phosphoinositide- 3-kinase (PI3K) activation. The main objective of the study described in this thesis is to understand how PI3K-controlled gene expression regulates the balance between proliferation and differentiation of erythroid progenitors. In particular, we studied the role of PI3K dependent control of mRNA translation.