Abstract
Germline deletion of Jak2 in mice results in embryonic lethality at E12.5 due to impaired hematopoiesis. However, the role that Jak2 might play in late gestation and postnatal life is unknown. To understand this, we utilized a conditional knockout approach that allowed for the deletion of Jak2 at various stages of prenatal and postnatal life. Specifically, Jak2 was deleted beginning at either mid/late gestation (E12.5), at postnatal day 4 (PN4), or at ∼2 months of age. Deletion of Jak2 beginning at E12.5 resulted in embryonic death characterized by a lack of hematopoiesis. Deletion beginning at PN4 was also lethal due to a lack of erythropoiesis. Deletion of Jak2 in young adults was characterized by blood cytopenias, abnormal erythrocyte morphology, decreased marrow hematopoietic potential, and splenic atrophy. However, death was observed in only 20% of the mutants. Further analysis of these mice suggested that the increased survivability was due to an incomplete deletion of Jak2 and subsequent re-population of Jak2 expressing cells, as conditional deletion in mice having one floxed Jak2 allele and one null allele resulted in a more severe phenotype and subsequent death of all animals. We found that the deletion of Jak2 in the young adults had a differential effect on hematopoietic lineages; specifically, conditional Jak2 deletion in young adults severely impaired erythropoiesis and thrombopoiesis, modestly affected granulopoiesis and monocytopoiesis, and had no effect on lymphopoiesis. Interestingly, while the hematopoietic organs of these mutant animals were severely affected by the deletion of Jak2, we found that the hearts, kidneys, lungs, and brains of these same mice were histologically normal. From this, we conclude that Jak2 plays an essential and non-redundant role in hematopoiesis during both prenatal and postnatal life and this has direct implications regarding the inhibition of Jak2 in humans.
Highlights
Hematopoiesis is the process whereby hematopoietic stem cells in the bone marrow give rise to the terminally differentiated cells in the peripheral blood
We found that germline deletion of Janus kinase 2 (Jak2) derived from the Jak2 conditional knockout (cKO) mice in our hands resulted in a phenotype that was identical to the previous Jak2 conventional knockouts, as all our Jak2 null embryos were dead and partially resorbed at E13.5 and the reason for death was impaired hematopoiesis (Figure S1)
Postnatal Life Results in Death due to Severe Anemia To investigate the importance of Jak2 during early postnatal life, TM was administered to ROSA26CreER/+;Jak2f/f and ROSA26+/ +;Jak2f/f mice beginning at postnatal day 4 (PN4)
Summary
Hematopoiesis is the process whereby hematopoietic stem cells in the bone marrow give rise to the terminally differentiated cells in the peripheral blood. The process is exquisitely controlled by a number of cytokines including granulocyte-macrophage colonystimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), erythropoietin (EPO), and thrombopoietin (TPO) to name a few. The binding of these cytokines to their cognate receptors on hematopoietic cells results in the activation of at least ten different Src family kinases and all four Janus family kinases within these cell types [1,2,3,4]. Janus kinase 2 (Jak2) is a member of the Janus family of tyrosine kinases It was cloned in 1992 and found to be ubiquitously expressed in a number of animal tissues including hematopoietic organs [5]. What role, if any, that Jak might play in hematopoiesis during the later stages of embryonic development, as well as in postnatal life, has not been previously explored
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