PMID:23544085

Citation	Park, SO, Wamsley, HL, Bae, K, Hu, Z, Li, X, Choe, SW, Slayton, WB, Oh, SP, Wagner, KU and Sayeski, PP (2013) Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS ONE 8:e59675
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.
Links	PubMed PMC3609865 Online version:10.1371/journal.pone.0059675
Keywords	Aging/pathology; Anemia/pathology; Animals; Animals, Newborn; Blood Cell Count; Embryo Loss/pathology; Embryonic Development/drug effects; Embryonic Development/genetics; Female; GTP-Binding Proteins/metabolism; Gene Deletion; Hematopoiesis/drug effects; Hematopoiesis/genetics; Hematopoietic Stem Cells/drug effects; Hematopoietic Stem Cells/metabolism; Hematopoietic Stem Cells/pathology; Humans; Interferon Regulatory Factor-1/metabolism; Janus Kinase 2/antagonists & inhibitors; Janus Kinase 2/genetics; Lymphocytes/drug effects; Lymphocytes/pathology; Mice; Mice, Knockout; Myeloid Progenitor Cells/drug effects; Myeloid Progenitor Cells/metabolism; Myeloid Progenitor Cells/pathology; Organ Specificity/drug effects; Pregnancy; Spleen/pathology; Survival Analysis; Tamoxifen/pharmacology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:JAK2		GO:0035166: post-embryonic hemopoiesis	ECO:0000315:		P		Figure 3: B) Representative peripheral blood films from both genotypes showing the presence of anemia, thrombocytopenia, and poikilocytosis in the Jak2 cKO mice, but not the controls. (C) Histologic sections of spleen found an abnormal splenic architecture in the Jak2 cKO mice characterized by atrophied and disorganized white pulp.(D) Representative bone marrow sections from both genotypes indicating increased adipose deposits in the Jak2 cKO mice, but not the controls. (E) Representative liver sections showing diffuse centrolobular vacuolar degeneration in the Jak2 cKO tissue, but not in the control tissue.	complete CACAO 9822
MOUSE:JAK2	involved_in	GO:0035166: post-embryonic hemopoiesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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