Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene

Article metrics

Abstract

ERYTHROID Krüppel-like factor (EKLF) was originally isolated from erythroid cell RNA by differential screening and shown to be erythroid-specific, although a low level of EKLF was found in mast cell lines1,2. EKLF contains three zinc-fingers homologous to those found in the Kriippel family of transcription factors. Because it binds the sequence CCACACCCT, EKLF may affect erythroid development as a result of its ability to bind to the CAC box in the promoter of the β-globin gene1,2. Mutation of this element leads to reduced pβ-globin expression3-5and it appears to mediate the effect of the globin locus control region on the promoter6. Here we inactivate the EKLF gene through insertion of a lacZ reporter gene by homologous recombination in embryonic stem (ES) cells. Heterozygous EKLF+/- mice show that the reporter gene is expressed in a developmental!) specific manner in all types of erythroblasts in the fetal liver and adult bone marrow. Homo-zygous EKLF-/- mice appear normal during the embryonic stage of haematopoiesis in the yolk sac, but develop a fatal anaemia during early fetal life when haematopoiesis has switched to the fetal liver. Enucleated erythrocytes are formed but these do not contain the proper amount of haemoglobin. We conclude that the transcription factor EKLF is essential for the final steps of definitive erythropoiesis in fetal liver.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Miller, I. S. & Bieker, J. J. Molec. cell. Biol. 13, 2776–2786 (1993).

  2. 2

    Feng, W. C., Southwood, C. M. & Bieker, J. J. J. biol. Chem. 269, 1492–1500 (1994).

  3. 3

    Orkin, S. H. et al. Nature 296, 627–631 (1982).

  4. 4

    Orkin, S. H., Antonarakis, S. E. & Kazazian, H. H. J. biol. Chem. 259, 8679–8681 (1984).

  5. 5

    Kulozik, A. E., Bellan-Koch, A., Bail, S., Kohne, E. & Kleihauer, E. Blood 77, 2054–2058 (1991).

  6. 6

    Antoniou, M. & Grosveld, F. Genes Dev. 4, 1007–1013 (1990).

  7. 7

    Kalderon, D., Roberts, B., Richardson, W. D. & Smith, A. E. Cell 39, 499–509 (1984).

  8. 8

    Thomas, K. R. & Capecchi, M. R. Cell 51, 503–512 (1987).

  9. 9

    Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Moule, M. Nature 326, 292–295 (1987).

  10. 10

    Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Nature 336, 348–352 (1988).

  11. 11

    Robertson, E. J. Teratocarcinomas and Embryonic Stem Cells (IRL, Oxford and Washington DC, 1987).

  12. 12

    Ploemacher, R. E., Van Soest, P. L., Boudewijn, A. & Neben, S. Leukaemia 7, 1374–1380 (1993).

  13. 13

    Wong, P. M. et al. Blood 62, 1280–1288 (1983).

  14. 14

    Chada, K. et al. Nature 314, 377–380 (1985).

  15. 15

    Epperly, B. R., Bergenhem, N. C. H., Venta, P. J. & Tashian, R. E. Gene 131, 249–253 (1994).

  16. 16

    Beaumont, C., Porcher, C., Picat, C., Nordmann, Y. & Grandchamp, B. J. biol. Chem. 264, 14829–14834 (1989).

  17. 17

    Eleouet, J. F. & Romeo, P. H. Eur. J. Biochem. 272, 763–770 (1993).

  18. 18

    Donze, D., Townes, T. & Bieker, J. J. biol. Chem. 270, 1955–1959 (1995).

  19. 19

    Behringer, R. R., Ryan, T. M. & Palmiter, R. D. Genes Dev. 4, 380–389 (1990).

  20. 20

    Enver, T., Raich, N. & Ebens, A. S. Nature 344, 309–313 (1990).

  21. 21

    Hanscombe, O. et al. Genes Dev. 5, 1387–1394 (1991).

  22. 22

    Bonnerot, C. & Nicholas, J. F. Meth. Emzym. 225, 451–469 (1993).

  23. 23

    Strouboulis, J., Dillon, N. & Grosveld, F. Genes Dev. 6, 1857–1864 (1992).

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nuez, B., Michalovich, D., Bygrave, A. et al. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature 375, 316–318 (1995) doi:10.1038/375316a0

Download citation

Further reading

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.