Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Jan 9;93(1):407–411. doi: 10.1073/pnas.93.1.407

Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders.

K Yoshida 1, T Taga 1, M Saito 1, S Suematsu 1, A Kumanogoh 1, T Tanaka 1, H Fujiwara 1, M Hirata 1, T Yamagami 1, T Nakahata 1, T Hirabayashi 1, Y Yoneda 1, K Tanaka 1, W Z Wang 1, C Mori 1, K Shiota 1, N Yoshida 1, T Kishimoto 1
PMCID: PMC40247  PMID: 8552649

Abstract

gp130 is a ubiquitously expressed signal-transducing receptor component shared by interleukin 6, interleukin 11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1. To investigate physiological roles of gp130 and to examine pathological consequences of a lack of gp130, mice deficient for gp130 have been prepared. Embryos homozygous for the gp130 mutation progressively die between 12.5 days postcoitum and term. On 16.5 days postcoitum and later, they show hypoplastic ventricular myocardium without septal and trabecular defect. The subcellular ultrastructures in gp130-/- cardiomyocytes appear normal. The mutant embryos have greatly reduced numbers of pluripotential and committed hematopoietic progenitors in the liver and differentiated lineages such as T cells in the thymus. Some gp130-/- embryos show anemia due to impaired development of erythroid lineage cells. These results indicate that gp130 plays a crucial role in myocardial development and hematopoiesis during embryogenesis.

Full text

PDF
409

Images in this article

409Fig. 2
on p.409
410Fig. 6
on p.410

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akira S., Nishio Y., Inoue M., Wang X. J., Wei S., Matsusaka T., Yoshida K., Sudo T., Naruto M., Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994 Apr 8;77(1):63–71. doi: 10.1016/0092-8674(94)90235-6. [DOI] [PubMed] [Google Scholar]
  2. Chen Z., Friedrich G. A., Soriano P. Transcriptional enhancer factor 1 disruption by a retroviral gene trap leads to heart defects and embryonic lethality in mice. Genes Dev. 1994 Oct 1;8(19):2293–2301. doi: 10.1101/gad.8.19.2293. [DOI] [PubMed] [Google Scholar]
  3. Chien K. R., Zhu H., Knowlton K. U., Miller-Hance W., van-Bilsen M., O'Brien T. X., Evans S. M. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol. 1993;55:77–95. doi: 10.1146/annurev.ph.55.030193.000453. [DOI] [PubMed] [Google Scholar]
  4. Davis S., Aldrich T. H., Stahl N., Pan L., Taga T., Kishimoto T., Ip N. Y., Yancopoulos G. D. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science. 1993 Jun 18;260(5115):1805–1808. doi: 10.1126/science.8390097. [DOI] [PubMed] [Google Scholar]
  5. Hirota H., Yoshida K., Kishimoto T., Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4862–4866. doi: 10.1073/pnas.92.11.4862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kastner P., Grondona J. M., Mark M., Gansmuller A., LeMeur M., Decimo D., Vonesch J. L., Dollé P., Chambon P. Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell. 1994 Sep 23;78(6):987–1003. doi: 10.1016/0092-8674(94)90274-7. [DOI] [PubMed] [Google Scholar]
  7. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  8. Kopf M., Baumann H., Freer G., Freudenberg M., Lamers M., Kishimoto T., Zinkernagel R., Bluethmann H., Köhler G. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994 Mar 24;368(6469):339–342. doi: 10.1038/368339a0. [DOI] [PubMed] [Google Scholar]
  9. Levéen P., Pekny M., Gebre-Medhin S., Swolin B., Larsson E., Betsholtz C. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 1994 Aug 15;8(16):1875–1887. doi: 10.1101/gad.8.16.1875. [DOI] [PubMed] [Google Scholar]
  10. Lütticken C., Wegenka U. M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Yasukawa K., Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994 Jan 7;263(5143):89–92. doi: 10.1126/science.8272872. [DOI] [PubMed] [Google Scholar]
  11. Maeda T., Yamaguchi M., Taga T., Kishimoto T., Wada K., Ikegami H., Kurachi H., Miyake A. Decidua is a possible source of serum mouse soluble interleukin-6 receptor (msIL-6R): gestational profile of serum msIL-6R concentration. Biochem Biophys Res Commun. 1994 Dec 15;205(2):998–1003. doi: 10.1006/bbrc.1994.2765. [DOI] [PubMed] [Google Scholar]
  12. Mansour S. L., Thomas K. R., Capecchi M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  13. Masu Y., Wolf E., Holtmann B., Sendtner M., Brem G., Thoenen H. Disruption of the CNTF gene results in motor neuron degeneration. Nature. 1993 Sep 2;365(6441):27–32. doi: 10.1038/365027a0. [DOI] [PubMed] [Google Scholar]
  14. Murakami M., Hibi M., Nakagawa N., Nakagawa T., Yasukawa K., Yamanishi K., Taga T., Kishimoto T. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993 Jun 18;260(5115):1808–1810. doi: 10.1126/science.8511589. [DOI] [PubMed] [Google Scholar]
  15. Nakajima T., Kinoshita S., Sasagawa T., Sasaki K., Naruto M., Kishimoto T., Akira S. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2207–2211. doi: 10.1073/pnas.90.6.2207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Narazaki M., Witthuhn B. A., Yoshida K., Silvennoinen O., Yasukawa K., Ihle J. N., Kishimoto T., Taga T. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2285–2289. doi: 10.1073/pnas.91.6.2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pennica D., King K. L., Shaw K. J., Luis E., Rullamas J., Luoh S. M., Darbonne W. C., Knutzon D. S., Yen R., Chien K. R. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1142–1146. doi: 10.1073/pnas.92.4.1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pennica D., Shaw K. J., Swanson T. A., Moore M. W., Shelton D. L., Zioncheck K. A., Rosenthal A., Taga T., Paoni N. F., Wood W. I. Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem. 1995 May 5;270(18):10915–10922. doi: 10.1074/jbc.270.18.10915. [DOI] [PubMed] [Google Scholar]
  19. Rumyantsev P. P. Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol. 1977;51:186–273. [PubMed] [Google Scholar]
  20. Russell E. S. Hereditary anemias of the mouse: a review for geneticists. Adv Genet. 1979;20:357–459. [PubMed] [Google Scholar]
  21. Saito M., Yoshida K., Hibi M., Taga T., Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992 Jun 15;148(12):4066–4071. [PubMed] [Google Scholar]
  22. Scott E. W., Simon M. C., Anastasi J., Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science. 1994 Sep 9;265(5178):1573–1577. doi: 10.1126/science.8079170. [DOI] [PubMed] [Google Scholar]
  23. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar]
  24. Stahl N., Farruggella T. J., Boulton T. G., Zhong Z., Darnell J. E., Jr, Yancopoulos G. D. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995 Mar 3;267(5202):1349–1353. doi: 10.1126/science.7871433. [DOI] [PubMed] [Google Scholar]
  25. Stewart C. L., Kaspar P., Brunet L. J., Bhatt H., Gadi I., Köntgen F., Abbondanzo S. J. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992 Sep 3;359(6390):76–79. doi: 10.1038/359076a0. [DOI] [PubMed] [Google Scholar]
  26. Sucov H. M., Dyson E., Gumeringer C. L., Price J., Chien K. R., Evans R. M. RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev. 1994 May 1;8(9):1007–1018. doi: 10.1101/gad.8.9.1007. [DOI] [PubMed] [Google Scholar]
  27. Sui X., Tsuji K., Tanaka R., Tajima S., Muraoka K., Ebihara Y., Ikebuchi K., Yasukawa K., Taga T., Kishimoto T. gp130 and c-Kit signalings synergize for ex vivo expansion of human primitive hemopoietic progenitor cells. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2859–2863. doi: 10.1073/pnas.92.7.2859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Suzuki H., Yasukawa K., Saito T., Narazaki M., Hasegawa A., Taga T., Kishimoto T. Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal. Eur J Immunol. 1993 May;23(5):1078–1082. doi: 10.1002/eji.1830230515. [DOI] [PubMed] [Google Scholar]
  29. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  30. Yoshida K., Chambers I., Nichols J., Smith A., Saito M., Yasukawa K., Shoyab M., Taga T., Kishimoto T. Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways. Mech Dev. 1994 Feb;45(2):163–171. doi: 10.1016/0925-4773(94)90030-2. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES