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(DeltaKD)) we show a role for MEKK1 in definitive mouse erythropoiesis. Although Mekk1(DeltaKD) mice are alive and fertile on a 129 x C57/BL6 background, the frequency of Mekk1(DeltaKD) embryos that develop past embryonic day (E) 14.5 is dramatically reduced when backcrossed into the C57/BL6 background. At E13.5, Mekk1(DeltaKD) embryos have normal morphology but are anemic due to failure of definitive erythropoiesis. When Mekk1(DeltaKD) 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.
Bonnesen
Barbara
B
Institute of Molecular Biology and Physiology, Department of Immunology, University of Copenhagen, Denmark.
Orskov
Cathrine
C
Rasmussen
Susanne
S
Holst
Peter Johannes
PJ
Christensen
Jan Pravsgaard
JP
Eriksen
Karsten Wessel
KW
Qvortrup
Klaus
K
Odum
Niels
N
Labuda
Tord
T
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000196:embryology* / Q000473:pathology; D004920:Erythropoiesis / Q000235:genetics*; D006411:Hematopoiesis, Extramedullary / Q000235:genetics*; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000196:embryology* / Q000473:pathology; D016031:Liver Transplantation / Q000379:methods; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
D006454:Hemoglobins; D004247:DNA; D048728:MAP Kinase Kinase Kinase 1