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.

  • Original Paper
  • Published:

The MEK-1/ERKs signalling pathway is differentially involved in the self-renewal of early and late avian erythroid progenitor cells

Abstract

Making decisions between self-renewal and differentiation is a central ability of stem cells. Elucidation of molecular networks governing this decision is therefore of prime importance. A model of choice to explore this question is represented by chicken erythroid progenitors, in which self-renewal versus differentiation as well as progenitor maturation are regulated by external factor combinations. We used this system to study whether similar or different signalling pathways were involved in the self-renewal of early, immature or more mature erythroid progenitors. We show that a transforming growth factor (TGF)-α-activated Ras/MEK-1/ERK1/2 pathway is strictly required for immature self-renewing cells but becomes fully dispensable when those cells are induced to differentiate. Consequently, pharmacological inhibition of this pathway led to spontaneous differentiation, only dependent on the presence of survival signals. Conversely, ectopic expression of a constitutive form of MEK-1 stimulates renewal and arrests differentiation process. Finally, we demonstrate that the ERK/MAPK signalling pathway is required in early but not in late primary erythroid progenitors, which can be turned into each other by different growth factor combinations specifically driving their renewal. To the best of our knowledge, this is the first description of a central role of ERK/MAPK signalling in regulating progenitor plasticity in the same cell type under different environmental conditions.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Bartunek P, Pichlikova L, Stengl G, Boehmelt G, Martin FH, Beug H, Dvorak M and Zenke M . (1996). Cytokine, 8, 14–20.

  • Bauer A, Gandrillon O, Samarut J and Beug H . (2001). Hematopoiesis: a Developmental Approach. Zon, L. (ed) Oxford University Press: New York, pp. 368–390.

    Google Scholar 

  • Bauer A, Mikulits W, Lagger G, Stengl G, Brosch G and Beug H . (1998). EMBO J., 17, 4291–4303.

  • Bauer A, Tronche F, Wessely O, Kellendonk C, Reichardt HM, Steinlein P, Schutz G and Beug H . (1999). Genes Dev., 13, 2996–3002.

  • Bogdan S and Klambt C . (2001). Curr. Biol., 11, R292–R295.

  • Bourgin C, Bourette R, Mouchiroud G and Arnaud S . (2000). FEBS Lett., 480, 113–117.

  • Brunet A, Pages G and Pouyssegur J . (1994). Oncogene, 9, 3379–3387.

  • Chang L and Karin M . (2001). Nature, 410, 37–40.

  • Chow SC, Weis M, Kass GE, Holmstrom TH, Eriksson JE and Orrenius S . (1995). FEBS Lett., 364, 134–138.

  • Dolznig H, Boulme F, Stangl K, Deiner EM, Mikulits W, Beug H and Mullner EW . (2001). FASEB J., 15, 1442–1444.

  • Dolznig H, Habermann B, Stangl K, Deiner EM, Moriggl R, Beug H and Mullner EW . (2002). Curr. Biol., 12, 1076–1085.

  • Dudley DT, Pang L, Decker SJ, Bridges AJ and Saltiel AR . (1995). Proc. Natl. Acad. Sci. USA, 92, 7686–7689.

  • Fairbairn LJ, Cowling GJ, Reipert BM and Dexter TM . (1993). Cell, 74, 823–832.

  • Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA and Trzaskos JM . (1998). J. Biol. Chem., 273, 18623–18632.

  • Frelinger AL, Du III XP, Plow EF and Ginsberg MH . (1991). J. Biol. Chem., 266, 17106–17111.

  • Gandrillon O, Ferrand N, Michaille J-J, Roze L, Zile MH and Samarut J . (1994). Oncogene, 9, 749–758.

  • Gandrillon O, Jurdic P, Benchaibi M, Xiao J-H, Ghysdael J and Samarut J . (1987). Cell, 49, 687–697.

  • Gandrillon O and Samarut J . (1998). Oncogene, 16, 563–574.

  • Gandrillon O, Schmidt U, Beug H and Samarut J . (1999). EMBO J., 18, 2764–2781.

  • Hayman MJ, Meyer S, Martin F, Steinlein P and Beug H . (1993). Cell, 74, 157–169.

  • Heinrich R, Neel BG and Rapoport TA . (2002). Mol. Cell, 9, 957–970.

  • Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA and Lemischka IR . (2002). Science, 298, 601–604.

  • Johnson GL and Lapadat R . (2002). Science, 298, 1911–1912.

  • Kahn P, Frykberg L, Brady C, Stanley I, Beug H, Vennstrom B and Graf T . (1986). Cell, 45, 349–356.

  • Kohl NE, Wilson FR, Mosser SD, Giuliani E, deSolms SJ, Conner MW, Anthony NJ, Holtz WJ, Gomez RP, Lee TJ, Smith RL, Graham SL, Hartman GD, Gibbs SB and Oliff A . (1994). Proc. Natl. Acad. Sci. USA, 91, 9141–9145.

  • Kowenz E, Leutz A, Doderlein G, Graf T and Beug H . (1987). Modern Trends in Human Leukemia VII, Vol. 31: Hamatol. Bluttransfus. Neth R, Gallo, RC, Greaves MF and Kabisch H. (eds). Springer Verlag: Heidelberg, pp. 199–209.

    Book  Google Scholar 

  • Lacoste-Eleaume AS, Bleux C, Quere P, Coudert F, Corbel C and Kanellopoulos-Langevin C . (1994). Exp. Cell Res., 213, 198–209.

  • Lesault I, Quang CT, Frampton J and Ghysdael J . (2002). EMBO J., 21, 694–703.

  • Marshall CJ . (1995). Cell, 80, 179–185.

  • Matsuzaki T, Aisaki K, Yamamura Y, Noda M and Ikawa Y . (2000). Oncogene, 19, 1500–1508.

  • Nagata Y, Takahashi N, Davis RJ and Todokoro K . (1998). Blood, 92, 1859–1869.

  • Nishigaki K, Hanson C, Ohashi T, Thompson D, Muszynski K and Ruscetti S . (2000). J. Virol., 74, 3037–3045.

  • Pages G, Brunet A, L'Allemain G and Pouyssegur J . (1994). EMBO J., 13, 3003–3010.

  • Pouyssegur J, Volmat V and Lenormand P . (2002). Biochem. Pharmacol., 64, 755–763.

  • Quang CT, Wessely O, Pironin M, Beug H and Ghysdael J . (1997). EMBO J., 16, 5639–5653.

  • Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC and Melton DA . (2002). Science, 298, 597–600.

  • Samarut J and Gazzolo L . (1982). Cell, 28, 921–929.

  • Schoeberl B, Eichler-Jonsson C, Gilles ED and Muller G . (2002). Nat. Biotechnol., 20, 370–375.

  • Somervaille TC, Linch DC and Khwaja A . (2001). Blood, 98, 1374–1381.

  • Steinlein P, Deiner E, Leutz A and Beug H . (1994). Growth Factors, 10, 1–16.

  • Steinlein P, Wessely O, Meyer S, Deiner EM, Hayman MJ and Beug H . (1995). Curr. Biol., 5, 191–204.

  • Tamir A, Petrocelli T, Stetler K, Chu W, Howard J, Croix BS, Slingerland J and Ben-David Y . (2000). Cell Growth Differ., 11, 269–277.

  • Velculescu VE, Zhang L, Vogelstein B and Kinzler KW . (1995). Science, 270, 484–487.

  • Verfaillie CM . (2002). Trends Cell Biol., 12, 502–508.

  • Vlahos CJ, Matter WF, Hui KY and Brown RF . (1994). J. Biol. Chem., 269, 5241–5248.

  • von Lindern M, Deiner EM, Dolznig H, Parren-Van Amelsvoort M, Hayman MJ, Mullner EW and Beug H . (2001). Oncogene, 20, 3651–3664.

  • Watt FM and Hogan BL . (2000). Science, 287, 1427–1430.

  • Weissman IL . (2000). Cell, 100, 157–168.

  • Wessely O, Bauer A, Quang CT, Deiner EM, von Lindern M, Mellitzer G, Steinlein P, Ghysdael J and Beug H . (1999). Biol. Chem., 380, 187–202.

  • Wessely O, Deiner EM, Beug H and von Lindern M . (1997). EMBO J., 16, 267–280.

  • Witt O, Sand K and Pekrun A . (2000). Blood, 95, 2391–2396.

  • Zochodne B, Truong AH, Stetler K, Higgins RR, Howard J, Dumont D, Berger SA and Ben-David Y . (2000). Oncogene, 19, 2296–2304.

Download references

Acknowledgements

We thank all of those who are cited in the ‘Material and methods’ section for their generous gifts; Michèle Weiss for her assistance with FACS analysis; Edmund Derrington for manuscript corrections and all the members of the CGMC and specially the ‘hematopoiesis subsection’ for their invaluable help in setting up things. The work in our laboratory is supported by the Ligue contre le cancer (Comité Départemental du Rhône), the CNRS, the UCBL, the Région Rhône-Alpes (Programme Emergence), the Fondation de France and the Association pour la Recherche contre le Cancer. SD is a fellow from the Ligue contre le cancer (Comité départemental de l'Yonne) and the Association pour la Recherche contre le Cancer. FD is a fellow from the EU RTN program ‘Hematopoiesis’ (contract HPRN-CT-2000-00083). Work in the HB laboratory was supported by the above EU grant and by the Fonds zur Förderung der wissenschaftlichen Forschung Austria, (SFB 006).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Olivier Gandrillon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dazy, S., Damiola, F., Parisey, N. et al. The MEK-1/ERKs signalling pathway is differentially involved in the self-renewal of early and late avian erythroid progenitor cells. Oncogene 22, 9205–9216 (2003). https://doi.org/10.1038/sj.onc.1207049

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207049

Keywords

This article is cited by

Search

Quick links