Generation and characterization of Jak1 deficient mic

A recently discovered signal transduction pathway, the JAK-STAT pathway, has been implicated in mediating many, if not all, the signaling events necessary for cytokine specific gene induction. Critical to this pathway are two families of proteins, first, a set of transcription factors known as the Signal Transducers and Activators of Transcription (STATs) and second, a set of protein tyrosine kinases known as the Janus kinases (JAKs). Whereas analyses of JAK-STAT signaling have revealed that the STATs play a major role in mediating pathway specificity, the contributions of the JAKs to the pathway remain illdefined. To identify the non-redundant physiologic roles of an individual Janus kinase, Jak1 deficient mice were generated by homologous recombination techniques.;Jak1$sp{-/-}$ mice were 20-25% smaller than control littermates, failed to nurse, and died within 24 hours of birth. Cells derived from Jak1$sp{-/-}$ mice expressed no detectable Jak1 protein and exhibited no biological responses to IFN$alpha ,$ IFN$gamma ,$ or IL-10, thereby demonstrating an in vivo requirement for Jak1 for signal transduction through class II cytokine receptors. Analysis of peripheral blood from Jak1 deficient mice revealed normal numbers of RBCs, macrophages, and neutrophils. However Jak1$sp{-/-}$ mice exhibited 33-fold fewer thymocytes, 40-fold fewer mature B cells, and 10-fold fewer B cell precursors than control littermates. The origin of these deficits was determined to be a specific unresponsiveness of Jak1$sp{-/-}$ cells to cytokines which utilize the $gammasb{rm C}$ for signal transduction. In contrast, the mitogenic activities of other hematopoietic cytokines which can induce the activation of Jak1 in vitro, such as G-CSF and IL-3, were retained in the absence of Jak1. Thus the exclusive nonredundant role for Jak1 in hematopoiesis is restricted to promoting lymphoid development.;Further analyses of tissues derived from Jak1$sp{-/-}$ mice revealed a deficiency in IL-6 mediated STAT activation and a virtual elimination of LIF mediated STAT activation. The biologic significance of these signaling deficiencies was demonstrated by the ability of LIF or a combination of IL-6 and IL-6R$alpha$ to promote the survival of sensory neurons derived from dorsal root ganglia of Jak1$sp{+/-}$ mice but not Jak1$sp{-/-}$ mice. Further studies on sensory neurons revealed that Jak1 is essential for JAK-dependent biologic responses to all the known cytokines which utilize gp130 and the LIFR$beta$ for signal transduction. Taken together, these studies establish that Jak1 plays obligatory and restricted roles in promoting IFN-mediated protective responses, lymphocyte development, and neuronal survival.