Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway

• Published in: Cell Vol. 84; no. 3; pp. 431 - 442
• Main Authors: Meraz, Marco A, White, J.Michael, Sheehan, Kathleen C.F, Bach, Erika A, Rodig, Scott J, Dighe, Anand S, Kaplan, Daniel H, Riley, Joan K, Greenlund, Andrew C, Campbell, Dayle, Carver-Moore, Karen, DuBois, Raymond N, Clark, Ross, Aguet, Michel, Schreiber, Robert D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.02.1996
• Subjects: Animals; Base Sequence; Cytokines - pharmacology; Cytopathogenic Effect, Viral; DNA Probes - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; DNA-Binding Proteins - physiology; Female; Gene Targeting; Humans; Interferon-alpha - pharmacology; Interferon-gamma - pharmacology; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Rats; Signal Transduction - genetics; Signal Transduction - immunology; Signal Transduction - physiology; STAT1 Transcription Factor; Trans-Activators - genetics; Trans-Activators - immunology; Trans-Activators - physiology; Vesicular stomatitis Indiana virus - immunology; Vesicular stomatitis Indiana virus - pathogenicity
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)81288-X

The JAK–STAT signaling pathway has been implicated in mediating biologic responses induced by many cytokines. However, cytokines that promote distinct cellular responses often activate identical STAT proteins, thereby raising the question of how specificity is manifest within this signaling pathway. Here we report the generation and characterization of mice deficient in STAT1. STAT1-deficient mice show no overt developmental abnormalities, but display a complete lack of responsiveness to either IFNα or IFNγ and are highly sensitive to infection by microbial pathogens and viruses. In contrast, these mice respond normally 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 unexpected level of physiologic specificity for STAT1 action.