and Functional Redundancy in Erythropoiesis.

Several studies have established the crucial role of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway in hematopoietic cell proliferation and differentiation. MEK1 and MEK2 phosphorylate and activate ERK1 and ERK2. However, whether MEK1 and MEK2 differentially regulate these processes is unknown. To define the function of genes in the activation of the ERK pathway during hematopoiesis, we generated a mutant mouse line carrying a hematopoietic-specific deletion of the gene function in a null background. Inactivation of both and genes resulted in death shortly after birth with a severe anemia revealing the essential role of the ERK pathway in erythropoiesis. and functional ablation also affected lymphopoiesis and myelopoiesis. In contrast, mice that retained one functional (1) or (1) allele in hematopoietic cells were viable and fertile. 1 and 1 mutants showed mild signs of anemia and splenomegaly, but the half-life of their red blood cells and the response to erythropoietic stress were not altered, suggesting a certain level of redundancy for sustaining functional erythropoiesis. However, subtle differences in multipotent progenitor distribution in the bone marrow were observed in 1 mice, suggesting that the two genes might differentially regulate early hematopoiesis.