Permissive role of thrombopoietin and granulocyte colony-stimulating factor emcepetors in hematopoietic cell fate decisions in vivo

摘要

The question of whether extracellular signals influence hematopoiesis by instructing stem cells to commit to a specific hematopoietic lineage (instructive model) or solely by permitting the survival and proliferation of predetermined progenitors (permissive model) has been controversial since the discovery of lineage-dominant hematopoietic cytokines. To study the potential role of cytokines and their receptors in hematopoietic cell fate decisions, we used homologous recom- bination to replace the thrombopoietin receptor gene (mpl) with a chimeric construct encoding the extracellular domain or mpl and the cytoplasmic domain of the granulocyte colony- stimulating factor receptor (G-CSFR). This chimeric receptor binds thrombopoietin but signals through the G-CSFR intra- cellular domain. We found that, despite the absence of a functional mpl signaling domain,homozygous knock-in mice had a normal platelet count. indicating that in vivo the cytoplasmic domain of G-CSFR can functionally replace mpl signaling to support normal megakaryopoiesis and platelet formation. This finding is compatible with the permissive model, according to which cytokine receptors provide a non- specific survival or proliferation signal, and argues against an instructive role of mpl or G-CSFR in hematopoietic cell fate decisions.