Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)-Deficient Mice

  • Ashley R. Dunn
  • Graham J. Lieschke
Part of the Contemporary Immunology book series (CONTIM)


Granulocyte-macrophage colony stimulating factor (GM-CSF) is a secreted glycoprotein hemopoietic growth factor (124 amino acids in mouse and 127 amino acids in human) that in vitro stimulates the survival, proliferation, and function of myeloid cells (For review, see ref. 1). GM-CSF has a broad range of actions on target cells that include neutrophils, eosinophils, macrophages, erythroid progenitors, megakaryocyte progenitors, and antigen-presenting dendritic cells (For review, see ref. 2). The potency of GM-CSF in vivo has been demonstrated by generating GM-CSF transgenic mice (3) and by reconstituting mice with marrow cells previously infected with a recombinant retrovirus expressing GM-CSF (4). The hemopoietic system of mice exposed to excess levels of GM-CSF in these ways is profoundly affected with increases in both progenitor cells and granulocytes and macrophages. These animal models suggest that GM-CSF excess results in a myeloproliferative syndrome, but this does not lead to leukemia. However, preleukemic growth factor-dependent clones infected with recombinant retrovirus encoding GM-CSF are able to proliferate in the absence of exogenous GM-CSF and are uniformly leukemogenic in the syngeneic mouse (5). To establish the normal physiological role of GM-CSF we (6) and others (7) generated GM-CSF deficient mice by gene targeting in embryonic stem cells.


Deficient Mouse Lamellar Body Pulmonary Alveolar Proteinosis Pulmonary Pathology Lymphoid Infiltration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gasson, J. C. (1991) Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood 77, 1131–1145.PubMedGoogle Scholar
  2. 2.
    Nicola, N. A. (1994) Granulocyte-macrophage colony stimulating factor (GM-CSF), in Guidebook to Cytokines and Their Receptors ( Nicola, N. N., ed.), Sambrook and Tooze, Oxford University Press, Oxford, UK, pp. 171–173.Google Scholar
  3. 3.
    Lang, R. A., Metcalf, D., Cuthbertson, R. A., Lyons, I., Stanley, E., Kelso, A., Kannourakis, G., Williamson, D. J., Klintworth, G. K., Gonda, T. J., and Dunn, A. R. (1987) Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness and fatal syndrome of tissue damage. Cell 51, 675–686.PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson, G. R., Gonda, T. J., Metcalf, D., Hariharan, I. K., and Cory, S. (1989) A lethal myeloproliferative syndrome in mice transplanted with a retrovirus expressing granulocyte-macrophage colony stimulating factor. EMBO J. 8, 441–448.PubMedGoogle Scholar
  5. 5.
    Lang, R. A., Metcalf, D., Gough, N. M., Dunn, A. R., and Gonda, T. J. (1985) Expression of a hemopoietic growth factor cDNA in a factor-dependent cell line results in autonomous growth and tumorigenicity. Cell 43, 531–542.PubMedCrossRefGoogle Scholar
  6. 6.
    Stanley, E., Lieschke, G. J., Grail, D., Metcalf, D., Hodgson, G., Gall, J. A. M., Maher, D. W., Cebon, J., Sinickas, V., and Dunn, A. R. (1994) Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl. Acad. Sci. USA 91, 5592–5596.PubMedCrossRefGoogle Scholar
  7. 7.
    Dranoff, G., Crawford, A. D., Sadelain, M., Ream, B., Rashid, A., Bronson, R. T., Dickersin, G. R., Bachurski, C. J., Mark, E. L., Whitsett, J. A., and Mulligan, R. C. (1994) Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716.PubMedCrossRefGoogle Scholar
  8. 8.
    Barlow, D. P., Bucan, M., Lehrach, H. H. B. L., and Gough, N. M. (1987) Close physical and genetic linkage between the murine hematopoietic growth factor genes GM-CSF and multi-CSF (IL-3). EMBO J. 6, 617–623.PubMedGoogle Scholar
  9. 9.
    Stanley, E., Metcalf, D., Sobieszczuk, P., Gough, N. M., and Dunn, A. R. (1985) The structure and expression of the murine gene encoding granulocyte-macrophage colony stimulating factor: evidence for utilization of alternative promoters. EMBO J. 4, 2569–2573.PubMedGoogle Scholar
  10. 10.
    Miyatake, S., Otsuka, T., Yokota, T., Lee, F., and Arai, K. (1985) Structure of the chromosomal gene for granulocyte-macrophage colony stimulating factor: comparison of the mouse and human genes. EMBO J. 4, 2561–2568.PubMedGoogle Scholar
  11. 11.
    Caux, C., Dezutter-Dambuyant, C., Schmitt, D., and Banchereau, J. (1992) GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360, 258–261.PubMedCrossRefGoogle Scholar
  12. 12.
    Ikegami, M., Ueda, T., Hull, W., Whitsett, J. A., Mulligan, R. C., Dranoff, G., and Jobe, A. (1996) Surfactant metabolism in transgenic mice after granulocyte-macrophage colony stimulating factor ablation. Am. J. Physiol. 270, (Lung Cell. Mol. Physiol. 14, L650–L658.Google Scholar
  13. 13.
    Rosen, S. H., Castleman, B., and Liebow, A. A. (1958) Pulmonary alveolar proteinosis. N. Engl. J. Med. 258, 1123–1142.PubMedCrossRefGoogle Scholar
  14. 14.
    Doyle, A. P., Balcerzak, S. P., Wells, C. L., and Crittenden, J. O. (1963) Pulmonary alveolar proteinosis with hematologic disorders. Arch. Intern. Med. 112, 940–946.PubMedCrossRefGoogle Scholar
  15. 15.
    Colon, A. R., Lawrence, R. D., Mills, S. D., and O’Donnell, E. J. (1971) Childhood pulmonary alveolar proteinosis (PAP). Am. J. Dis. Child 121, 481–485.PubMedGoogle Scholar
  16. 16.
    Bilyk, N., Mackenzie, J. S., Papadimitriou, J. M., and Holt, P. G. (1988) Functional studies on macrophage populations in the airways and the lung wall of SPF mice in the steady state and during respiratory virus infection. Immunology 65, 417–425.PubMedGoogle Scholar
  17. 17.
    Beck, J. M., Warnock, M. L., Curtis, J. L., Sniezek, M. J., Arraj-Peffer, S. M., Kaltreider, H. B., and Shellito, J. E. (1991) Inflammatory responses to Pneumocystis carinii in mice selectively depleted of helper T lymphocytes. Am. J. Respir. Cell Mol. Biol. 5, 186–197.PubMedGoogle Scholar
  18. 18.
    Lieschke, G. J., Stanley, E., Grail, D., Hodgson, G., Sinickas, V., Gall, J. A. M., Sinclair, R. A., and Dunn, A. R. (1994) Mice lacking both macrophage-and granulocyte-macrophage colony-stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease. Blood 84, 27–35.PubMedGoogle Scholar
  19. 19.
    Wiktor-Jedrzejczak, W., Bartocci, A., Ferrante, A. W., Jr., Ahmed-Ansari, A., Sell, K. W., Pollard, J. W., and Staley, E. R. (1990) Total absence of colony stimulating activity 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl. Acad. Sci. USA 87, 4828–4832.PubMedCrossRefGoogle Scholar
  20. 20.
    Yoshida, H., Hayashi, S., Kunisada, T., Ogawa, M., Nishikawa, S., Okamura, H., Sudo, T., Shultz, L. D., and Nishikawa, S. (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444.PubMedCrossRefGoogle Scholar
  21. 21.
    Nilsson, S. K., Lieschke, G. J., Garcia-Wijnen, C. C., Williams, B., Tzelepis, D., Hodgson, G., Grail, D., Dunn, A. R., and Bertoncello, I. (1995) Granulocyte-macrophage colony-stimulating factor is not responsible for the correction of haematopoietic deficiencies in the maturing op/op mouse. Blood 86, 66–72.PubMedGoogle Scholar
  22. 22.
    Begg, S. K. and Bertoncello, I. (1993) The hematopoietic deficiencies in osteopetrotic (op/op) mice are not permanent, but progressively correct with age. Exp. Hematol. 21, 493–495.PubMedGoogle Scholar
  23. 23.
    Begg, S. K., Radley, J. M., Pollard, J. W., Chisolm, O. T., Stanley, E. R., and Bertoncello, I. (1993) Delayed hematopoietic development in osteopetrotic (op/op) mice. J. Exp. Med. 177, 237–242.PubMedCrossRefGoogle Scholar
  24. 24.
    Nilsson, S. K. and Bertoncello, I. (1994) Age-related changes in extramedullary hematopoiesis in the spleen of normal and perturbed osteopetrotic (op/op) mice. Exp. Hematol. 22, 377–383.PubMedGoogle Scholar
  25. 25.
    Felix, R., Cecchini, M. G., and Fleisch, H. (1990) Macrophage colony stimulating factor restores in vivo bone resorption in the osteopetrotic mouse. Endocrinology 127, 2592–2594.PubMedCrossRefGoogle Scholar
  26. 26.
    Wiktor-Jedrzejczak, W., Urbanowska, E., Aukerman, S. L., Pollard, J. W., Stanley, E. R., Ralph, P., Ansari, A. A., Sell, K. W., and Szperl, M. (1991) Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local development and humoral requirements for this growth factor. Exp. Hematol. 19, 1049–1054.PubMedGoogle Scholar
  27. 27.
    Wiktor-Jedrzejczak, W., Urbanowska, E., and Szperl, M. (1994) Granulocyte-macrophage colony stimulating factor corrects macrophage deficiencies, but not osteopetrosis, in the colony stimulating factor-1- deficient op/op mouse. Endocrinology 134, 1932–1935.PubMedCrossRefGoogle Scholar
  28. 28.
    Lieschke, G. J., Grail, D., Metcalf, D., Hodgson, G., Stanley, E. G., Sinickas, V., Folwer, K. J., and Dunn, A. R. (1944) Mice lacking in granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84, 1737–1746.Google Scholar
  29. 29.
    Hayashida, K., Kitamura, T., Gorman, D. M., Arai, K., Yokata, T., and Miyajima, A. (1990) Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony stimulating factor (GM-CSF): reconstruction of a high affinity GM-CSF receptor. Proc. Natl. Acad. Sci. USA 87, 9655–9659.PubMedCrossRefGoogle Scholar
  30. 30.
    Nishinakamura, R., Nakayama, N., Hirabayashi, Y., Inoue, T., Aud, D., McNeil, T., Azuma, S., Yoshida, S., Toyoda, Y., Arai, K-I., Miyajima, A., and Murray, R. (1995) Mice deficient for the IL-3/GM-CSF/IL-5 ßc receptor exhibit lung pathology and impaired immune response, while 13u,3 receptor-deficient mice are normal. Immunity 2, 211–222.PubMedCrossRefGoogle Scholar
  31. 31.
    Robb, L., Drinkwater, C. C., Metcalf, D., Li, R., Köntgen, F., Nicola, N. A., and Begley, C. G. (1995) Hematopoietic and lung abnormalities in mice with a null mutation of the common f3 subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. Proc. Natl. Acad. Sci. USA 92, 9565–9569.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Ashley R. Dunn
  • Graham J. Lieschke

There are no affiliations available

Personalised recommendations