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Mouse Fetal Liver Culture System to Dissect Target Gene Functions at the Early and Late Stages of Terminal Erythropoiesis
Published on: September 9, 2014
MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver
Barbara Bonnesen1, Cathrine Orskov, Susanne Rasmussen
1Institute of Molecular Biology and Physiology, Department of Immunology, University of Copenhagen, Denmark.
Abstract:
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.
Insights
Mitogen-activated protein kinase kinase kinase 1 (MEKK1) deficiency impairs definitive erythropoiesis in mice. This failure is linked to defective macrophage-mediated nuclear DNA destruction during red blood cell development.
Area of Science:
- Cell Biology
- Developmental Biology
- Hematology
Background:
- Mitogen-activated protein kinase kinase kinase 1 (MEKK1) is a kinase that activates c-Jun N-terminal kinase (JNK).
- MEKK1 is known to play roles in inflammatory responses and cell motility.
- Its role in erythropoiesis, the development of red blood cells, is not well understood.
Purpose of the Study:
- To investigate the role of MEKK1 kinase activity in definitive mouse erythropoiesis.
- To determine the underlying mechanisms of erythropoiesis failure in MEKK1-deficient mice.
Main Methods:
- Utilized mice deficient for MEKK1 kinase activity (Mekk1(DeltaKD)).
- Analyzed embryonic development and red blood cell production in Mekk1(DeltaKD) embryos.
- Performed fetal liver cell transplantation experiments.
- Conducted immunohistochemical and hemoglobin chain transcription analysis.
Main Results:
- Mekk1(DeltaKD) embryos showed reduced survival past embryonic day 14.5 when backcrossed to C57/BL6.
- Embryos at E13.5 were anemic, exhibiting a failure of definitive erythropoiesis despite normal morphology.
- Transplantation of Mekk1(DeltaKD) fetal liver cells into wild-type hosts resulted in mature red blood cell generation, indicating non-cell-autonomous function.
- Definitive erythropoiesis failure was associated with deficient enucleation activity.
Conclusions:
- MEKK1 kinase activity is crucial for definitive erythropoiesis in mice.
- The failure in erythropoiesis is attributed to insufficient macrophage-mediated nuclear DNA destruction, impacting enucleation.
- MEKK1 likely functions in a non-cell-autonomous manner, possibly influencing macrophage function during erythropoiesis.
