TARGETED DISRUPTION OF THE STAT1 GENE IN MICE REVEALS UNEXPECTED PHYSIOLOGICAL SPECIFICITY IN THE JAK-STAT SIGNALING PATHWAY

The JAK-STAT signaling pathway has been implicated in mediating biolog ic responses induced by many cytokines. However, cytokines that promot e distinct cellular responses often activate identical STAT proteins, thereby raising the question of how specificity is manifest within thi s signaling pathway. Here we report the generation and characterizatio n of mice deficient in STAT1. STAT1-deficient mice show no overt devel opmental abnormalities, but display a complete lack of responsiveness to either IFN alpha or IFN gamma and are highly sensitive to infection by microbial pathogens and viruses. In contrast, these mice respond n ormally to several other cytokines that activate STAT1 in vitro. These observations document that STAT1 plays an obligate and dedicated role in mediating IFN-dependent biologic responses and reveal an unexpecte d level of physiologic specificity for STAT1 action.