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Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene


The production of blood cells is sustained throughout the lifetime of an individual by haematopoietic stem cells (HSCs)1. Specification of HSCs from mesoderm during embryonic development requires the stem cell leukaemia SCL/tal-1 gene product2,3,4,5,6. Forced expression of SCL/tal-1 strongly induces blood formation in embryos, indicating that this gene has a dominant role in commitment to haematopoiesis7,8. In the adult haematopoietic system, expression of SCL/tal-1 is enriched in HSCs and multipotent progenitors, and in erythroid and megakaryocytic lineages9,10,11, consistent with roles for this factor in adult haematopoiesis. Here we assess by conditional gene targeting whether SCL/tal-1 is required continuously for the identity and function of HSCs. We find that SCL/tal-1 is dispensable for HSC engraftment, self-renewal and differentiation into myeloid and lymphoid lineages; however, the proper differentiation of erythroid and megakaryocytic precursors is dependent on SCL/tal-1. Thus, SCL/tal-1 is essential for the genesis of HSCs, but its continued expression is not essential for HSC functions. These findings contrast with lineage choice mechanisms, in which the identity of haematopoietic lineages requires continuous transcription factor expression12,13.

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Figure 1: Inducible inactivation of the SCL/tal-1 locus in vivo.
Figure 2: Continuing lymphopoiesis and myelopoiesis in the absence of SCL/tal-1.
Figure 3: Requirement for SCL in erythroid and megakaryocytic differentiation in vitro.
Figure 4: Requirement for SCL in erythroblast maturation in the bone marrow.
Figure 5: Haematopoietic stem cell function in the absence of SCL/tal-1.


  1. 1

    Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287, 1442–1446 (2000)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Shivdasani, R. A., Mayer, E. L. & Orkin, S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373, 432–443 (1995)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Porcher, C. et al. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86, 47–57 (1996)

    CAS  Article  Google Scholar 

  4. 4

    Porcher, C., Liao, E. C., Fujiwara, Y., Zon, L. I. & Orkin, S. H. Specification of hematopoietic and vascular development by the bHLH transcription factor SCL without direct DNA binding. Development 126, 4603–4615 (1999)

    CAS  PubMed  Google Scholar 

  5. 5

    Robb, L. et al. Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc. Natl Acad. Sci. USA 92, 7075–7079 (1995)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Robb, L. et al. The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. EMBO J. 15, 4123–4129 (1996)

    CAS  Article  Google Scholar 

  7. 7

    Gering, M., Rodaway, A. R., Gottgens, B., Patient, R. K. & Green, A. R. The SCL gene specifies haemangioblast development from early mesoderm. EMBO J. 17, 4029–4045 (1998)

    CAS  Article  Google Scholar 

  8. 8

    Mead, P. E., Deconinck, A. E., Huber, T. L., Orkin, S. H. & Zon, L. I. Primitive erythropoiesis in the Xenopus embryo: the synergistic role of LMO-2, SCL and GATA-binding proteins. Development 128, 2301–2308 (2001)

    CAS  PubMed  Google Scholar 

  9. 9

    Elefanty, A. G. et al. Characterization of hematopoietic progenitor cells that express the transcription factor SCL, using a lacZ ‘knock-in’ strategy. Proc. Natl Acad. Sci. USA 95, 11897–11902 (1998)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C. & Melton, D. A. ‘Stemness’: transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Orkin, S. H. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet. 1, 57–64 (2000)

    CAS  Article  Google Scholar 

  13. 13

    Mikkola, I., Heavey, B., Horcher, M. & Busslinger, M. Reversion of B cell commitment upon loss of Pax5 expression. Science 297, 110–113 (2002)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Gu, H., Marth, J. D., Orban, P. C., Mossmann, H. & Rajewsky, K. Deletion of a DNA polymerase-β gene segment in T cells using cell type-specific gene targeting. Science 265, 103–106 (1994)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Socolovsky, M. et al. Ineffective erythropoiesis in Stat5a-/-5b-/- mice due to decreased survival of early erythroblasts. Blood 98, 3261–3273 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Wadman, I. A. et al. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 16, 3145–3157 (1997)

    CAS  Article  Google Scholar 

  18. 18

    Yamada, Y. et al. The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc. Natl Acad. Sci. USA 95, 3890–3895 (1998)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998)

    CAS  PubMed  Google Scholar 

  20. 20

    Robertson, S. M., Kennedy, M., Shannon, J. M. & Keller, G. A transitional stage in the commitment of mesoderm to hematopoiesis requiring the transcription factor SCL/tal-1. Development 127, 2447–2459 (2000)

    CAS  PubMed  Google Scholar 

  21. 21

    Faloon, P. et al. Basic fibroblast growth factor positively regulates hematopoietic development. Development 127, 1931–1941 (2000)

    CAS  PubMed  Google Scholar 

  22. 22

    Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Ying, Q. L., Nichols, J., Evans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Cantor, A. B., Katz, S. G. & Orkin, S. H. Distinct domains of the GATA-1 cofactor FOG-1 differentially influence erythroid versus megakaryocytic maturation. Mol. Cell. Biol. 22, 4268–4279 (2002)

    CAS  Article  Google Scholar 

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We thank D. Traver for discussions; J. Dailey and S. Lazo-Kallanian for cell sorting; K. Rajewsky for MxCre mice; and A. Williams and S. Galusha for assistance in generating the conditional SCL/tal-1 strain. H.K.A.M. received support from the Finnish Cultural Foundation and the Academy of Finland. This work was supported in part by a grant from the NIH to S.H.O., who is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Stuart H. Orkin.

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Mikkola, H., Klintman, J., Yang, H. et al. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421, 547–551 (2003).

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