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