Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway.
The JAK-STAT signaling pathway has been implicated in mediating biological 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 IFN alpha or IFN gamma 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.
Meraz
M A
MA
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
White
J M
JM
Sheehan
K C
KC
Bach
E A
EA
Rodig
S J
SJ
Dighe
A S
AS
Kaplan
D H
DH
Riley
J K
JK
Greenlund
A C
AC
Campbell
D
D
Carver-Moore
K
K
DuBois
R N
RN
Clark
R
R
Aguet
M
M
Schreiber
R D
RD
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral; D015342:DNA Probes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D005260:Female; D018390:Gene Targeting; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051381:Rats; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology / Q000472:pathogenicity
D016207:Cytokines; D015342:DNA Probes; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C494081:Stat1 protein, rat; D015534:Trans-Activators; D007371:Interferon-gamma