Ectoderm specific deletion of Jak2 results in developmental and neuronal abnormalities (1121.4)

Janus kinase 2 (Jak2) is a non‐receptor tyrosine kinase that is expressed in a number of mammalian tissues. Within the central nervous system, Jak2 has been associated with neuroproliferation, glial differentiation, synaptic plasticity, energy homeostasis, brain tumors, and neurodegenerative disorders. Recent clinical studies that have used Jak2 inhibitor therapy for the treatment of hematological disorders have noted an adverse event in the form of neuropathies in various ectoderm derived sensory organs as well as confusional states of mind. However, the precise physiological/patho‐physiological roles that Jak2 plays in ectodermal derived organs is not clear. Here, we hypothesized that Jak2 plays a critical role in the development of the ectoderm in mice. To test this, we created a tissue specific knockout mouse that lacks Jak2 in ectodermal derived organs. When compared to wild type littermate controls, these mice have a number of abnormalities in their reproductive organs, eyes, and digits. In addition, the mice had a marked alopecia and a behavioral disorder characterized by aimless and repeated circling within the cage. Interestingly, the penetrance of phenotypes was observed in 30% ‐ 50% of the homozygous mutant mice, thereby suggesting a role for other modifiers in these abnormalities. Collectively, these results indicate that Jak2 plays a critical role in the development of the mammalian ectoderm. Furthermore, because of the current use of Jak2 inhibitors in humans, these mice can serve as a valuable research tool for investigating neurotoxicity that is secondary to the loss of Jak2 function in ectoderm tissues. Grant Funding Source : Supported by NIH and AHA