Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

An intrinsic but cell-nonautonomous defect in GATA-1-overexpressing mouse erythroid cells

Nature volume 406, pages 519–524 (2000)Cite this article

An Erratum to this article was published on 23 November 2000

Abstract

GATA-1 is a tissue-specific transcription factor that is essential for the production of red blood cells1,2. Here we show that overexpression of GATA-1 in erythroid cells inhibits their differentiation, leading to a lethal anaemia. Using chromosome-X-inactivation of a GATA-1 transgene and chimaeric animals, we show that this defect is intrinsic to erythroid cells, but nevertheless cell nonautonomous. Usually, cell nonautonomy is thought to reflect aberrant gene function in cells other than those that exhibit the phenotype3. On the basis of our data, we propose an alternative mechanism in which a signal originating from wild-type erythroid cells restores normal differentiation to cells overexpressing GATA-1 in vivo. The existence of such a signalling mechanism indicates that previous interpretations of cell-nonautonomous defects may be erroneous in some cases and may in fact assign gene function to incorrect cell types.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: GATA-1 overexpression in vivo.
Figure 2: GATA-1 transgene is subject to X-inactivation.
Figure 3: Cells overexpressing GATA-1 contribute to erythroid lineage in adult chimaeric mice.
Figure 4: GATA-1 overexpressing CFU-Es fail to differentiate and undergo apoptosis in vitro.
Figure 5: A simplified model of the erythroblastic island.

Similar content being viewed by others

References

  1. Pevny, L. et al. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349, 257–260 (1991).

    Article  ADS  CAS  Google Scholar 

  2. Weiss, M. J., Keller, G. & Orkin, S. H. Novel insights into erythroid development revealed through in vitro differentiation of GATA-1- embryonic stem cells. Genes Dev. 8, 1184–1197 (1994).

    Article  CAS  Google Scholar 

  3. Rossant, J. & Spence, A. Chimera and mosaics in mouse mutant analysis. Trends Genet. 14, 358– 363 (1998).

    Article  CAS  Google Scholar 

  4. Weiss, M. J. & Orkin, S. H. Transcription factor GATA-1 permits survival and maturation of erythroid precursors by preventing apoptosis. Proc. Natl Acad. Sci. USA 92, 9623– 9627 (1995).

    Article  ADS  CAS  Google Scholar 

  5. Takahashi, S. et al. Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo. Blood 92 , 434–442 (1998).

    Article  CAS  Google Scholar 

  6. Whyatt, D. J. et al. The level of the tissue-specific factor GATA-1 affects the cell-cycle machinery. Genes Funct. 1, 11 –24 (1997).

    Article  CAS  Google Scholar 

  7. Kuroda, M. I. & Meller, V. H. Transient Xist-ence. Cell 91, 9–11 ( 1997).

    Article  CAS  Google Scholar 

  8. Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C. & Orkin, S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl Acad. Sci. USA 93, 12355– 12358 (1996).

    Article  ADS  CAS  Google Scholar 

  9. Tsai, F. -Y., Browne, C. P. & Orkin, S. H. Knock-in mutation of transcription factor GATA-3 into the GATA-1 locus: partial rescue of GATA-1 loss of function in erythroid cells. Dev. Biol. 196, 218– 227 (1998).

    Article  CAS  Google Scholar 

  10. Panning, B., Dausman, J. & Jaenisch, R. X chromosome inactivation is mediated by Xist RNA stabilization. Cell 90, 907– 916 (1997).

    Article  CAS  Google Scholar 

  11. Sheardown, S. A. et al. Stabilization of Xist RNA mediates initiation of X chromosome inactivation. Cell 91, 99– 107 (1997).

    Article  CAS  Google Scholar 

  12. Hendriks, R. W. et al. Inactivation of Btk by insertion by insertion of lacZ reveals defects in B cell development only past the pre-B cell stage. EMBO J. 15, 4862–4872 (1996).

    Article  CAS  Google Scholar 

  13. Cormack, D. Time-lapse characterization of erythrocytic colony-forming cells in plasma cultures. Exp. Hematol. 4, 319– 327 (1976).

    CAS  PubMed  Google Scholar 

  14. Sawada, K., Krantz, S. B., Dessypris, E N., Koury, S. T. & Sawyer, S. T. Human colony-forming units-erythroid do not require acessory cells but do require direct interaction with insulin-like growth factor 1 and/or insulin for erythroid development. J. Clin. Invest. 83, 1701–1709 ( 1989).

    Article  CAS  Google Scholar 

  15. Apfeld, J. & Kenyon, C. Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span. Cell 95, 199–210 ( 1998).

    Article  CAS  Google Scholar 

  16. Dubart, A., Romeo, P. H., Vainchenker, W. & Dumenil, D. Constitutive expression of GATA-1 interferes with the cell-cycle regulation. Blood 87, 3711–3721 (1996).

    Article  CAS  Google Scholar 

  17. Briegel, K. et al. Regulation and function of transcription factor GATA-1 during red blood cell differentiation. Development 122, 3839–3850 (1996).

    Article  CAS  Google Scholar 

  18. Bessis, M., Lessin, L. S. & Beutler, E. in Hematology (eds Williams, W. J., Beutler, E., Erslev, A. J. & Lichtman, M. A.) 257–279 (McGraw-Hill, New York, 1983).

    Google Scholar 

  19. Bernard, J. The erythroblastic island: past and future. Blood Cells 17, 5–14 (1991).

    CAS  PubMed  Google Scholar 

  20. De Maria, R. et al. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401, 489– 493 (1999).

    Article  ADS  CAS  Google Scholar 

  21. Williams, B. O. et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J. 13, 4251–4259 (1994).

    Article  CAS  Google Scholar 

  22. Maandag, E. C. et al. Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J. 13, 4260–4268 (1994).

    Article  CAS  Google Scholar 

  23. Hu, N., Gulley, M. L., Kung, J. T. & Lee, E. Y.-H. Retinoblastoma gene deficiency has mitogenic but not tumorigenic effects on erythropoiesis. Cancer Res. 57, 4123– 4129 (1997).

    CAS  PubMed  Google Scholar 

  24. Elefanty, A. G., Antoniou, M., Custodio, N., Carmo-Fonseca, M. & Grosveld, F. G. GATA transcription factors associate with a novel class of nuclear bodies in erythroblasts and megakaryocytes. EMBO J. 15, 319–333 (1996).

    Article  CAS  Google Scholar 

  25. Nagamine, C. M., Chan, K. M., Kozak, C. A. & Lau, Y. F. Chromosome mapping and expression of a putative testis-determining gene in the mouse. Science 243, 80– 83 (1989).

    Article  ADS  CAS  Google Scholar 

  26. Andrews, N. C. & Faller, D. V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 19, 2499 (1991).

    Article  CAS  Google Scholar 

  27. Pandolfi, P. P. et al. Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nature Genet. 11, 40–44 ( 1995).

    Article  CAS  Google Scholar 

  28. Mulder, M. P. et al. Positional mapping of loci in the DiGeorge critical region at chromosome 22q11 using a new marker (D22S183). Human Genet. 96, 133–141 ( 1995).

    Article  CAS  Google Scholar 

  29. Wijgerde, M., Grosveld, F. & Fraser, P. Transcription complex stability and chromatin dynamics in vivo. Nature 377, 209– 213 (1995).

    Article  ADS  CAS  Google Scholar 

  30. Wong, P. M. C., Chung, S. W., Chui, D. H. K. & Eaves, C. J. Properties of the earliest clonogenic hemopoietic procursors to appear in the developing murine yolk sac. Proc. Natl Acad. Sci. USA 83, 3851–3854 (1986).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Bernards for his critical evaluation, discussions and materials contributing to this work. We also thank M. von Lindern, T. Verkerk, V. Lui, R. Delwel, S. Verbakel, G. Zafarana, N. Gillemans, D. Meijer, T. Stijnen, E. Dzierzak, E. Noteboom, R. Kerkhoven, J.-H. Dannenberg, H. te Riele and members of R. Bernards’ laboratory for advice, assistance and materials at various stages of the project. D.W. is supported by a long-term EMBO Fellowship. F.L. is supported by NWO (Netherlands). R.H. is supported by KNAW (Netherlands). NWO (Netherlands) and the EC supported this work.

Author information

Authors and Affiliations

  1. Division of Molecular Carcinogenesis The Netherlands Cancer Institute, Amsterdam , 1066 CX, The Netherlands

    David Whyatt

  2. Department of Cell Biology and Genetics, Erasmus University, Medical Genetics Centre, PO Box 1738, Rotterdam, 3000 DR, The Netherlands

    Fokke Lindeboom, Alar Karis, Rita Ferreira, Eric Milot, Rudi Hendriks, Marella de Bruijn, An Langeveld, Joost Gribnau, Frank Grosveld & Sjaak Philipsen

Authors
  1. David Whyatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fokke Lindeboom
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alar Karis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rita Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eric Milot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rudi Hendriks
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marella de Bruijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. An Langeveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joost Gribnau
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frank Grosveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sjaak Philipsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Grosveld.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whyatt, D., Lindeboom, F., Karis, A. et al. An intrinsic but cell-nonautonomous defect in GATA-1-overexpressing mouse erythroid cells. Nature 406, 519–524 (2000). https://doi.org/10.1038/35020086

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35020086

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing