MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver

Mitogen-activated protein kinase/extracellular signal to regulated kinase (MEK) kinase 1 (MEKK1) is a c-Jun N-terminal kinase (JNK) activating kinase known to be implicated in proinflammatory responses and cell motility. Using mice deficient for MEKK1 kinase activity (Mekk1(Delta KD)) we show a role for MEKK1 in definitive mouse erythropoiesis. Although Mekk1(Delta KD) mice are alive and fertile on a 129 x C57/BL6 background, the frequency of Mekk(1 Delta KD) embryos that develop past embryonic day (E) 14.5 is dramatically reduced when backcrossed into the C57/BL6 background. At E13.5, Mekk(1 Delta KD) embryos have normal morphology but are anemic due to failure of definitive erythropoiesis. When Mekk1(Delta KD) fetal liver cells were transferred to lethally irradiated wild-type hosts, mature red blood cells were generated from the mutant cells, suggesting that MEKK1 functions in a non-cell-autonomous manner. Based on immunohistochemical and hemoglobin chain transcription analysis, we propose that the failure of definitive erythropoiesis is due to a deficiency in enucleation activity caused by insufficient macrophage-mediated nuclear DNA destruction.