Abstract
Interferons (IFNs) are key cytokines in the innate immune response that also bridge the gap to adaptive immunity. Signaling upon stimulation by IFN type I, II and III is mediated by the Jak-Stat pathway. STAT1 is activated by all three IFN receptor complexes and absence of STAT1 from mice increases their susceptibility to pathogens. In addition, depending on the setting, STAT1 can act as tumor suppressor or oncogene. Here we report the generation and detailed functional characterization of a conditional Stat1 knockout mouse. We show the integrity of the conditional Stat1 locus and report successful in vivo deletion by means of a ubiquitous and a tissue-specific Cre recombinase. The conditional Stat1 null allele represents an important tool for identifying novel and cell-autonomous STAT1 functions in infection and cancer.
This is a preview of subscription content, log in via an institution to check access.
References
Chapgier A, Kong XF, Boisson-Dupuis S, Jouanguy E, Averbuch D, Feinberg J, Zhang SY, Bustamante J, Vogt G, Lejeune J, Mayola E, de Beaucoudrey L, Abel L, Engelhard D, Casanova JL (2009) A partial form of recessive STAT1 deficiency in humans. J Clin Invest 119:1502–1514. doi:10.1172/JCI37083
Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I (1999) Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 8:265–277. doi:10.1023/A:1008942828960
Decker T, Muller M, Stockinger S (2005) The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol 5:675–687. doi:10.1038/nri1684
Der SD, Zhou A, Williams BR, Silverman RH (1998) Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA 95:15623–15628. doi:10.1073/pnas.95.26.15623
Donnelly RP, Kotenko SV (2010) Interferon-lambda: a new addition to an old family. J Interferon Cytokine Res 30:555–564. doi:10.1089/jir.2010.0078
Durbin JE, Hackenmiller R, Simon MC, Levy DE (1996) Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84:443–450. doi:10.1016/S0092-8674(00)81288-X
Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 95:7556–7561. doi:10.1073/pnas.95.13.7556
Karaghiosoff M, Steinborn R, Kovarik P, Kriegshauser G, Baccarini M, Donabauer B, Reichart U, Kolbe T, Bogdan C, Leanderson T, Levy D, Decker T, Muller M (2003) Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat Immunol 4:471–477. doi:10.1038/ni910
Klover PJ, Muller WJ, Robinson GW, Pfeiffer RM, Yamaji D, Hennighausen L (2010) Loss of STAT1 from mouse mammary epithelium results in an increased neu-induced tumor burden. Neoplasia 12:899–905. doi:10.1593/neo.10716
Kovacic B, Stoiber D, Moriggl R, Weisz E, Ott RG, Kreibich R, Levy DE, Beug H, Freissmuth M, Sexl V (2006) STAT1 acts as a tumor promoter for leukemia development. Cancer Cell 10:77–87. doi:10.1016/j.ccr.2006.05.025
Kovarik P, Stoiber D, Novy M, Decker T (1998) Stat1 combines signals derived from IFN-gamma and LPS receptors during macrophage activation. EMBO J 17:3660–3668. doi:10.1093/emboj/17.13.3660
Kristensen IA, Veirum JE, Moller BK, Christiansen M (2010) Novel STAT1 alleles in a patient with impaired resistance to mycobacteria. J Clin Immunol doi:10.1007/s10875-010-9480-8
Leitner NR, Strobl B, Bokor M, Painz R, Kolbe T, Rulicke T, Muller M, Karaghiosoff M (2006) A time- and dose-dependent STAT1 expression system. BMC Biotechnol 6:48. doi:10.1186/1472-6750-6-48
Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662. doi:10.1038/nrm909
Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RD (1996) Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431–442. doi:10.1016/S0092-8674(00)81288-X
Pham CT, MacIvor DM, Hug BA, Heusel JW, Ley TJ (1996) Long-range disruption of gene expression by a selectable marker cassette. Proc Natl Acad Sci USA 93:13090–13095. doi:10.1073/pnas.93.23.13090
Rajewsky K, Gu H, Kuhn R, Betz UA, Muller W, Roes J, Schwenk F (1996) Conditional gene targeting. J Clin Invest 98:600–603. doi:10.1172/JCI118828
Schwenk F, Baron U, Rajewsky K (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23:5080–5081. doi:10.1093/nar/23.24.5080
Yang J, Stark GR (2008) Roles of unphosphorylated STATs in signaling. Cell Res 18:443–451. doi:10.1038/cr.2008.41
Zhang SY, Boisson-Dupuis S, Chapgier A, Yang K, Bustamante J, Puel A, Picard C, Abel L, Jouanguy E, Casanova JL (2008) Inborn errors of interferon (IFN)-mediated immunity in humans: insights into the respective roles of IFN-alpha/beta, IFN-gamma, and IFN-lambda in host defense. Immunol Rev 226:29–40. doi:10.1111/j.1600-065X.2008.00698.x
Acknowledgments
This work was supported by grants from the Austrian Science Fund (SFB-F28) to M.M. and T.D., and from the Austrian Genome Research Programme GEN-AU II and III (Austromouse) to NRL, TR and MM. Biomodels Austria is an infrastructure project of the Austrian Federal Ministry for Science and Research (BM.W_Fa). We thank Kerstin Mair for assistance in cloning the targeting construct and Simone Müller for marker-assisted selection of mice used to establish a congenic strain. We are grateful to Claus Vogl for statistical support and to Graham Tebb and Birgit Strobl for critically reading the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Wallner, B., Leitner, N.R., Vielnascher, R.M. et al. Generation of mice with a conditional Stat1 null allele. Transgenic Res 21, 217–224 (2012). https://doi.org/10.1007/s11248-011-9519-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11248-011-9519-5