Jak2 Plays a Critical and Non-Redundant Role In Hematopoiesis throughout Pre- and Post-Natal Life

Abstract 2238

In early Jak2 murine models, conventional germline knockout of Jak2 tyrosine kinase resulted in embryonic lethality at E12.5 due to severe defects in hematopoiesis. However, what role, if any, that Jak2 plays in late gestational development and post natal life is currently unknown. To achieve some understanding of this, we utilized a conditional knockout approach that allowed for the temporal deletion of Jak2 at various stages of embryonic and postnatal growth. Specifically, Jak2 conditional knockout mice were produced by crossing estrogen receptor inducible Cre mice (RosaCreER) with loxP inserted Jak2 conditional knockout mice (FL/FL). Injection of the bigenic mice with tamoxifen (TM), a synthetic estrogen receptor modulator, accordingly results in a Jak2 null allele. TM was injected into pregnant dams at E12.5 and into postnatal mice at day 4 and day 60. The animals were then euthanized at E16.5 (late gestation), postnatal at day 18 (an active stage of postnatal development) and day 90 (adult stage), respectively. We found that deletion of Jak2 throughout all stages of murine development resulted in marked hypocellular bone marrow, significantly reduced spleen size, an absence of extramedullary hematopoiesis, and profound anemia. Analysis of peripheral blood samples indicated that the Jak2 null mice have significantly decreased hematocrits characterized by increased numbers of abnormal red blood cells that were either immature or lacking hemoglobin. Furthermore, the number of platelets was also significantly reduced in the null mice when compared to aged matched littermate controls. Overall, these results indicate that Jak2 plays a critical and non-redundant role in hematopoiesis throughout all stages of prenatal and postnatal life.